利用噬菌体展示技术筛选CRFR1肽类拮抗剂
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摘要
促肾上腺皮质激素释放因子(Corticotropin-releasing Factor,CRF)是由41个氨基酸组成的神经肽。是机体应激反应的关键因子,协调应激相关的自主神经、免疫、生理和行为反应。CRF是应激反应轴下丘脑-垂体-肾上腺轴(HPA轴)的起始因子,通过作用于垂体上的CRF受体1(Corticotropin-releasing Factor receptor,CRFR1),激活HPA轴。CRF受体是典型的G蛋白偶联受体,主要有CRFR1与CRFR2两种亚型。两种受体的信号传导途径相似,以AC-cAMP-PKA信号通路为主介导生物学效应。在长期应激条件下,CRF分泌过多,HPA轴功能亢进,介导了抑郁症等情感类疾病。重症抑郁症患者脑脊液中CRF含量过高,HPA轴功能亢进;crfr1基因敲除小鼠不易表现出焦虑样行为;CRFR1拮抗剂能够拮抗动物的抑郁样行为等证据都表明CRFR1有可能成为新一代抗抑郁症的靶标。尽管CRFR1拮抗剂在动物模型中显现出良好的抗抑郁作用,但在临床试验中表现出严重的毒性反应,使此类药物的研究不得不停止。小肽类药物具有活性高,副反应小等优势,越来越受到人们的重视,目前还没有关于CRFR1小肽类拮抗剂的报道。本课题利用经典的噬菌体展示技术筛选CRFR1肽类拮抗剂,希望筛选到毒副作用小的CRFR1小肽类拮抗剂,用于抑郁症的治疗与研究。
1.靶蛋白序列的分析和确定:CRFR1为典型的B1超家族G蛋白偶联受体,七次跨膜,N端位于细胞外,C端位于细胞内。CRFR1 EC1区是CRF及相关肽结合的关键区域,其中包含形成CRFR1结合构象的区域(Q43-N90)和CRFR1的选择性结合区域(R76-A89)。CRFR1与CRFR2具有>70%的同源性,其中EC1区同源性最低(60%)。因此根据重要结构域、同源性低、胞外区的原则,选取CRFR1的EC1区域(M 1-V118)作为靶蛋白。
2.靶蛋白的表达和纯化:将EC1的cDNA序列连接到原核表达载体pGEX-4T2上,并将其转化到BL21(DE3)感受态细胞中,用IPTG诱导融合蛋白GST-EC1188的表达。SDS-PAGE分析GST- EC1118蛋白主要以包涵体的形式表达。通过优化诱导条件都不能增加可溶性蛋白的表达。分析EC1的氨基酸序列,EC1的M1-N19区域和N108-V118区域富含疏水性氨基酸和含硫氨基酸,疏水键和二硫键过多容易导致包涵体的形成,影响蛋白的溶解性。因此在保证CRFR1的选择性结合区域完整的基础上,去除M1-N19与N108-V118区域,重新选择EC1(P20-N107)片段作为靶蛋白。重新构建原核表达载体pGEX-4T2-CRFR1 EC1(P20-N107),IPTG低温诱导GST-EC188蛋白的表达。将超声裂解后的上清液用GSTrap FF纯化柱纯化,SDS -PAGE分析鉴定纯化结果,最终获得高纯度的GST-EC188靶蛋白。
3.亲和肽的筛选:从Ph.D.-12和Ph.D.-C7C文库中筛选与靶蛋白结合的噬菌体克隆。将靶蛋白GST-EC188与GST固定到固相载体上,Ph.D.-12和Ph.D.-C7C文库先与GST蛋白孵育,将未与GST结合的噬菌体再与靶蛋白结合,洗掉非特异性结合的噬菌体,将特异性结合的噬菌体洗脱下来进行扩增,用于下一轮的筛选,筛选三轮。通过降低靶蛋白的浓度、增加洗脱强度、减少噬菌体与靶蛋白的孵育时间等措施优化筛选条件,筛选到结合力强的噬菌体克隆。用回收率%(回收滴度/投入滴×100)表示噬菌体的富集程度,Ph.D.-12文库第三轮的回收率%(4.2×10-3)是第一轮回收率%(5×10-5)的84倍;Ph.D.-C7C文库第三轮的回收率%(2.5×10-3)是第一轮回收率%(1.5×10-5)的167倍。结果证明经过三轮筛选,与靶蛋白特异性结合的噬菌体克隆得到富集。用ELISA法鉴定噬菌体克隆与靶蛋白的结合力,得到12个阳性克隆。用竞争性ELISA进一步验证亲和力,12个阳性克隆与CRFR1的结合表现为浓度依赖性。分别为Ph.D.-C7C文库1、2、6、7、9、12、14号克隆,Ph.D.-12文库2、5、14、15、16号克隆。分析阳性噬菌体展示肽的氨基酸序列。发现12个噬菌体展示肽均与CRF有一定的同源性,其中Ph.D.-C7C文库P2、P7、P14,Ph.D.-12文库P2、P15、P16与CRF的同源性最高,并且结合力较强。
4. HEK293-CRFR1稳定表达细胞株的建立:为鉴定筛选到的小肽的生物活性,构建了HEK293-CRFR1稳定表达细胞株。Western blotting与RT-PCR结果显示CRFR1蛋白表达,以3号克隆表达量高;荧光免疫结果显示CRFR1表达于细胞膜上。CRF刺激HEK293-CRFR1细胞释放cAMP的实验结果说明CRFR1不但稳定表达于HEK293细胞,并且具有功能(EC50 = (8.44±0.68)×10-9 M,n=3)。
5.亲和肽功能验证:初步验证12个阳性噬菌体展示肽对CRFR1功能的影响。利用原核表达载体pGEX-4T2,诱导表达与纯化融合表达蛋白GST-小肽,得到高纯度的GST-小肽。用cAMP释放试验验证GST-小肽对CRF刺激HEK293-CRFR1细胞释放cAMP的影响。结果显示,环七肽1、2、6、9、14号小肽,十二肽5、15、16号小肽表现不同程度的抑制作用,其中以十二肽P16抑制作用最强。GST蛋白可能会影响小肽与CRFR1的结合与作用,因此化学合成P16,进一步验证其功能。
6. P16拮抗效应及机制研究:
6.1验证P16对CRFR1的特异性抑制作用。用CRF刺激HEK293-CRFR1细胞释放cAMP,用P16拮抗此作用。结果显示在CRF(32 nM)存在的条件下,P16抑制CRF刺激HEK293-CRFR1细胞释放cAMP的作用,并且呈现浓度依赖性(IC50 = (1.36±0.60)×10-10 M,n=3)。在没有CRF作用下,不同浓度P16(5 pM~10 nM)对HEK293 -CRFR1细胞cAMP的基础水平没有影响。说明P16特异性地抑制CRFR1的功能。
6.2验证P16对CRFR2的选择性。CRFR2选择性激动剂UCN3刺激瞬时转染HE-K293-CRFR2细胞释放cAMP量效曲线拟合良好(EC50 = (3.65±0.25)×10-8 M , n= 3),说明CRFR2表达于HEK293细胞中,并且具有功能。用UCN3(144 nM)刺激瞬时转染HEK293-CRFR2细胞释放cAMP,同时加入P16测定对HEK293-CRFR2细胞释放cAMP的影响。结果显示不同浓度P16(1 pM~10μM)对UCN3刺激HEK293 -CRFR2细胞释放cAMP没有影响。说明P16对CRFR2的功能没有影响。
6.3验证P16对CRF刺激HEK293-CRFR1细胞释放cAMP量效曲线的影响。结果显示没有P16存在时,CRF量效曲线EC50 = (7.22±0.42)×10-8 M(n=3) ;在0.1 nM P16存在时,CRF量效曲线平行右移,EC50 = (1.10±0.25)×10-7 M (n=3) ;在1 nM P16存在时,CRF标准曲线平行右移幅度大于0.1 nM P16组, EC50=(1.50±0.38)×10-7 M(n=3)。说明P16竞争性地抑制CRF刺激HEK293-CRFR1细胞释放cAMP,P16是CRFR1的竞争性抑制剂。
综上所述,本研究建立在可溶性表达了CRFR1重要的结合区域EC1(P20-N107)的基础上,以EC1(P20-N107)为靶蛋白,从Ph.D.-12和Ph.D.-C7C文库中筛选到12个与CRFR1结合强的噬菌体克隆,初步验证小肽对CRFR1的作用,其中P16抑制活性最高。通过观察P16对稳定表达CRFR1的HEK293细胞的作用,发现P16以竞争性抑制的方式,选择性拮抗CRFR1功能,而对CRFR2功能没有明显影响。本研究工作利用噬菌体展示技术筛选到CRFR1特异性竞争性拮抗剂P16等小肽,为靶向CRFR1抗抑郁症小肽类药物的研发奠定了基础。
Corticotropin-releasing factor (CRF) is a 41-amino acid neuropeptide, originally isolated by Rivier and colleagues. CRF plays a key role in the coordination of neuroendocrine, autonomic, and behavioral responses to stress. In central nervous system, CRF is synthesized and released from parvocellular neurons of the paraventricular nucleus (PVN), bound to CRF receptors (CRFR) locate in anterior pituitary to activate the hypothalamus–pituitary–adrenocortical (HPA) system. CRF and CRF related peptides Urocortin I (UCN1), stresscopin-related peptide (UCN2) and stresscopin (UCN3) act mainly through CRF1 receptors (CRFR1) and CRF2 receptors (CRFR2). The human/rat CRF (h/rCRF) has 15 fold higher affinity for the CRFR1 than the CRFR2. CRFR1 and CRFR2 belong to the class B1 group of the G protein-coupled receptor (GPCR) superfamily. Both receptor subtypes are coupled to the same Gαproteins and signal through similar second messengers, such as the adenylyl cyclase-protein kinase A pathway by coupling with Gs and the phospholipase C-protein kinase C pathway by coupling with Gq.
Numerous studies suggest that CRFR1 receptors become the drug target for depression and anxiety. Clinical studies find high levels of CRF in the cerebrospinal fluid of depressed patients. Several selective CRFR1 nonpeptidic antagonists have been demonstrated antidepressant like efficacy in animal models. Mouse mutants lacking CRFR1, showed less stress-induced anxiety-like behavior compared with wild type animals. Since 1991, a large number of small molecule CRFR1 antagonists have been developed. Clinical datas of NBI-30775/RS121919 and NBI-34041 were published. Howere, the clinic research has been ended due to adverse side effects such as hepatotoxicity. There is no CRFR1 antagonist is on market so far. Small peptide drugs present a lot of advantages, such as mild side effects, high activity with low dose, generally non-immunogenic. Peptide drug development has gained more and more attention. The aim of this paper is to identify novel CRFR1 peptide antagonists from phage display library.
CRF1 receptor’s EC1 domain has no receptor activation, but it plays a key role in peptide ligand binding. The Gln43-Asn90 domain constituted the CRF1 receptor binding pocket, Arg76-Ala89 domain formed the CRF1 receptor ligand binding selectivity domain. So the eighty eight amino acids (Pro20–Asn107) of CRFR1 were selected for panning small peptides from Ph.D.-12 and Ph.D.-C7C. After three rounds panning, the binding positive phages were enriched. The coefficient of recovery of the Ph.D.-12 and Ph.D.-C7C increased approximately 84-fold and 167-fold respectively. Twelve phages were shown binding positive in dose dependent manner by ELISA. Twelve polypeptides share sequence homology with CRF, No2, No7, No14 of Ph.D.-C7C and No2, No15, No16 of Ph.D.-12 shared higher homology with CRF. The affinity of six phages for CRFR1 was higher than other phages, which shared lower homology with CRF.
We successfully constructed two cell strains which stably expressed pcDNA3.1-hCRFR1 and pcDNA3.1 in HEK293 cells respectively. Twelve polypeptide fragments were expressed and purified with the pronucleus expression vector pGEX-4T2. Twelve coexpression polypeptides could attenuate cAMP accumulation of HEK293-CRFR1 cells not HEK293-pcDNA3.1 cells induced by CRF (32 nM) in different degree. P16 was chemically synthesized due to higher inhibition. P16 shown strong inhibition of the cAMP formation of HEK293-hCRFR1 cells concentration -dependently induced by CRF (32 nM), but had no influence in the cAMP formation of HEK293-hCRFR1 at the absence of CRF. P16 could not inhibit the cAMP accumulation while HEK293-hCRFR2 cells were exposed to UCN3, the CRFR2 selective agonist. The cAMP accumulation concentration-responsive curve of CRF shifted right at the presence of P16 (0.1nM, 1nM), which suggested that P16 was the competitive antagonist of CRFR1. It is implied that P16 specifically bound to CRFR1, but not CRFR2, and competitively inhibited CRFR1 activation. We conclude that P16 is a selective and competitive antagonist of CRFR1. It has the potential to become a new and high activity antidepressant and antianxiety drug with little side effects.
1.靶蛋白序列的分析和确定:CRFR1为典型的B1超家族G蛋白偶联受体,七次跨膜,N端位于细胞外,C端位于细胞内。CRFR1 EC1区是CRF及相关肽结合的关键区域,其中包含形成CRFR1结合构象的区域(Q43-N90)和CRFR1的选择性结合区域(R76-A89)。CRFR1与CRFR2具有>70%的同源性,其中EC1区同源性最低(60%)。因此根据重要结构域、同源性低、胞外区的原则,选取CRFR1的EC1区域(M 1-V118)作为靶蛋白。
2.靶蛋白的表达和纯化:将EC1的cDNA序列连接到原核表达载体pGEX-4T2上,并将其转化到BL21(DE3)感受态细胞中,用IPTG诱导融合蛋白GST-EC1188的表达。SDS-PAGE分析GST- EC1118蛋白主要以包涵体的形式表达。通过优化诱导条件都不能增加可溶性蛋白的表达。分析EC1的氨基酸序列,EC1的M1-N19区域和N108-V118区域富含疏水性氨基酸和含硫氨基酸,疏水键和二硫键过多容易导致包涵体的形成,影响蛋白的溶解性。因此在保证CRFR1的选择性结合区域完整的基础上,去除M1-N19与N108-V118区域,重新选择EC1(P20-N107)片段作为靶蛋白。重新构建原核表达载体pGEX-4T2-CRFR1 EC1(P20-N107),IPTG低温诱导GST-EC188蛋白的表达。将超声裂解后的上清液用GSTrap FF纯化柱纯化,SDS -PAGE分析鉴定纯化结果,最终获得高纯度的GST-EC188靶蛋白。
3.亲和肽的筛选:从Ph.D.-12和Ph.D.-C7C文库中筛选与靶蛋白结合的噬菌体克隆。将靶蛋白GST-EC188与GST固定到固相载体上,Ph.D.-12和Ph.D.-C7C文库先与GST蛋白孵育,将未与GST结合的噬菌体再与靶蛋白结合,洗掉非特异性结合的噬菌体,将特异性结合的噬菌体洗脱下来进行扩增,用于下一轮的筛选,筛选三轮。通过降低靶蛋白的浓度、增加洗脱强度、减少噬菌体与靶蛋白的孵育时间等措施优化筛选条件,筛选到结合力强的噬菌体克隆。用回收率%(回收滴度/投入滴×100)表示噬菌体的富集程度,Ph.D.-12文库第三轮的回收率%(4.2×10-3)是第一轮回收率%(5×10-5)的84倍;Ph.D.-C7C文库第三轮的回收率%(2.5×10-3)是第一轮回收率%(1.5×10-5)的167倍。结果证明经过三轮筛选,与靶蛋白特异性结合的噬菌体克隆得到富集。用ELISA法鉴定噬菌体克隆与靶蛋白的结合力,得到12个阳性克隆。用竞争性ELISA进一步验证亲和力,12个阳性克隆与CRFR1的结合表现为浓度依赖性。分别为Ph.D.-C7C文库1、2、6、7、9、12、14号克隆,Ph.D.-12文库2、5、14、15、16号克隆。分析阳性噬菌体展示肽的氨基酸序列。发现12个噬菌体展示肽均与CRF有一定的同源性,其中Ph.D.-C7C文库P2、P7、P14,Ph.D.-12文库P2、P15、P16与CRF的同源性最高,并且结合力较强。
4. HEK293-CRFR1稳定表达细胞株的建立:为鉴定筛选到的小肽的生物活性,构建了HEK293-CRFR1稳定表达细胞株。Western blotting与RT-PCR结果显示CRFR1蛋白表达,以3号克隆表达量高;荧光免疫结果显示CRFR1表达于细胞膜上。CRF刺激HEK293-CRFR1细胞释放cAMP的实验结果说明CRFR1不但稳定表达于HEK293细胞,并且具有功能(EC50 = (8.44±0.68)×10-9 M,n=3)。
5.亲和肽功能验证:初步验证12个阳性噬菌体展示肽对CRFR1功能的影响。利用原核表达载体pGEX-4T2,诱导表达与纯化融合表达蛋白GST-小肽,得到高纯度的GST-小肽。用cAMP释放试验验证GST-小肽对CRF刺激HEK293-CRFR1细胞释放cAMP的影响。结果显示,环七肽1、2、6、9、14号小肽,十二肽5、15、16号小肽表现不同程度的抑制作用,其中以十二肽P16抑制作用最强。GST蛋白可能会影响小肽与CRFR1的结合与作用,因此化学合成P16,进一步验证其功能。
6. P16拮抗效应及机制研究:
6.1验证P16对CRFR1的特异性抑制作用。用CRF刺激HEK293-CRFR1细胞释放cAMP,用P16拮抗此作用。结果显示在CRF(32 nM)存在的条件下,P16抑制CRF刺激HEK293-CRFR1细胞释放cAMP的作用,并且呈现浓度依赖性(IC50 = (1.36±0.60)×10-10 M,n=3)。在没有CRF作用下,不同浓度P16(5 pM~10 nM)对HEK293 -CRFR1细胞cAMP的基础水平没有影响。说明P16特异性地抑制CRFR1的功能。
6.2验证P16对CRFR2的选择性。CRFR2选择性激动剂UCN3刺激瞬时转染HE-K293-CRFR2细胞释放cAMP量效曲线拟合良好(EC50 = (3.65±0.25)×10-8 M , n= 3),说明CRFR2表达于HEK293细胞中,并且具有功能。用UCN3(144 nM)刺激瞬时转染HEK293-CRFR2细胞释放cAMP,同时加入P16测定对HEK293-CRFR2细胞释放cAMP的影响。结果显示不同浓度P16(1 pM~10μM)对UCN3刺激HEK293 -CRFR2细胞释放cAMP没有影响。说明P16对CRFR2的功能没有影响。
6.3验证P16对CRF刺激HEK293-CRFR1细胞释放cAMP量效曲线的影响。结果显示没有P16存在时,CRF量效曲线EC50 = (7.22±0.42)×10-8 M(n=3) ;在0.1 nM P16存在时,CRF量效曲线平行右移,EC50 = (1.10±0.25)×10-7 M (n=3) ;在1 nM P16存在时,CRF标准曲线平行右移幅度大于0.1 nM P16组, EC50=(1.50±0.38)×10-7 M(n=3)。说明P16竞争性地抑制CRF刺激HEK293-CRFR1细胞释放cAMP,P16是CRFR1的竞争性抑制剂。
综上所述,本研究建立在可溶性表达了CRFR1重要的结合区域EC1(P20-N107)的基础上,以EC1(P20-N107)为靶蛋白,从Ph.D.-12和Ph.D.-C7C文库中筛选到12个与CRFR1结合强的噬菌体克隆,初步验证小肽对CRFR1的作用,其中P16抑制活性最高。通过观察P16对稳定表达CRFR1的HEK293细胞的作用,发现P16以竞争性抑制的方式,选择性拮抗CRFR1功能,而对CRFR2功能没有明显影响。本研究工作利用噬菌体展示技术筛选到CRFR1特异性竞争性拮抗剂P16等小肽,为靶向CRFR1抗抑郁症小肽类药物的研发奠定了基础。
Corticotropin-releasing factor (CRF) is a 41-amino acid neuropeptide, originally isolated by Rivier and colleagues. CRF plays a key role in the coordination of neuroendocrine, autonomic, and behavioral responses to stress. In central nervous system, CRF is synthesized and released from parvocellular neurons of the paraventricular nucleus (PVN), bound to CRF receptors (CRFR) locate in anterior pituitary to activate the hypothalamus–pituitary–adrenocortical (HPA) system. CRF and CRF related peptides Urocortin I (UCN1), stresscopin-related peptide (UCN2) and stresscopin (UCN3) act mainly through CRF1 receptors (CRFR1) and CRF2 receptors (CRFR2). The human/rat CRF (h/rCRF) has 15 fold higher affinity for the CRFR1 than the CRFR2. CRFR1 and CRFR2 belong to the class B1 group of the G protein-coupled receptor (GPCR) superfamily. Both receptor subtypes are coupled to the same Gαproteins and signal through similar second messengers, such as the adenylyl cyclase-protein kinase A pathway by coupling with Gs and the phospholipase C-protein kinase C pathway by coupling with Gq.
Numerous studies suggest that CRFR1 receptors become the drug target for depression and anxiety. Clinical studies find high levels of CRF in the cerebrospinal fluid of depressed patients. Several selective CRFR1 nonpeptidic antagonists have been demonstrated antidepressant like efficacy in animal models. Mouse mutants lacking CRFR1, showed less stress-induced anxiety-like behavior compared with wild type animals. Since 1991, a large number of small molecule CRFR1 antagonists have been developed. Clinical datas of NBI-30775/RS121919 and NBI-34041 were published. Howere, the clinic research has been ended due to adverse side effects such as hepatotoxicity. There is no CRFR1 antagonist is on market so far. Small peptide drugs present a lot of advantages, such as mild side effects, high activity with low dose, generally non-immunogenic. Peptide drug development has gained more and more attention. The aim of this paper is to identify novel CRFR1 peptide antagonists from phage display library.
CRF1 receptor’s EC1 domain has no receptor activation, but it plays a key role in peptide ligand binding. The Gln43-Asn90 domain constituted the CRF1 receptor binding pocket, Arg76-Ala89 domain formed the CRF1 receptor ligand binding selectivity domain. So the eighty eight amino acids (Pro20–Asn107) of CRFR1 were selected for panning small peptides from Ph.D.-12 and Ph.D.-C7C. After three rounds panning, the binding positive phages were enriched. The coefficient of recovery of the Ph.D.-12 and Ph.D.-C7C increased approximately 84-fold and 167-fold respectively. Twelve phages were shown binding positive in dose dependent manner by ELISA. Twelve polypeptides share sequence homology with CRF, No2, No7, No14 of Ph.D.-C7C and No2, No15, No16 of Ph.D.-12 shared higher homology with CRF. The affinity of six phages for CRFR1 was higher than other phages, which shared lower homology with CRF.
We successfully constructed two cell strains which stably expressed pcDNA3.1-hCRFR1 and pcDNA3.1 in HEK293 cells respectively. Twelve polypeptide fragments were expressed and purified with the pronucleus expression vector pGEX-4T2. Twelve coexpression polypeptides could attenuate cAMP accumulation of HEK293-CRFR1 cells not HEK293-pcDNA3.1 cells induced by CRF (32 nM) in different degree. P16 was chemically synthesized due to higher inhibition. P16 shown strong inhibition of the cAMP formation of HEK293-hCRFR1 cells concentration -dependently induced by CRF (32 nM), but had no influence in the cAMP formation of HEK293-hCRFR1 at the absence of CRF. P16 could not inhibit the cAMP accumulation while HEK293-hCRFR2 cells were exposed to UCN3, the CRFR2 selective agonist. The cAMP accumulation concentration-responsive curve of CRF shifted right at the presence of P16 (0.1nM, 1nM), which suggested that P16 was the competitive antagonist of CRFR1. It is implied that P16 specifically bound to CRFR1, but not CRFR2, and competitively inhibited CRFR1 activation. We conclude that P16 is a selective and competitive antagonist of CRFR1. It has the potential to become a new and high activity antidepressant and antianxiety drug with little side effects.
引文
[1] JOACHIM SPIESS JR, CATHERINE RIVIER, AND WYLIE VALE. Primary structure of corticotropmi-releasing factor from ovine hypothalamus [J]. Medical Sciences, 1981, 78:6517-21.
[2] Dautzenberg FM, Hauger RL. The CRF peptide family and their receptors: yet more partners discovered [J]. Trends Pharmacol Sci, 2002, 23(2):71-7.
[3] Bale TL, Vale WW. CRF and CRF receptors: role in stress responsivity and other behaviors [J]. Annu Rev Pharmacol Toxicol, 2004, 44:525-57.
[4] Stephen C. Heinrichs GFK. Corticotropin-Releasing Factor in Brain: A Role in Activation, Arousal, and Affect Regulation [J]. JPET, 2004, 311:427–40.
[5] Swanson LW, Sawchenko PE, Rivier J, Vale WW. Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study [J]. Neuroendocrinology, 1983, 36(3):165-86.
[6] Hauger RL, Risbrough V, Brauns O, Dautzenberg aFM. Corticotropin Releasing Factor (CRF) Receptor Signaling in the Central Nervous System: New Molecular Targets [J]. CNS Neurol Disord Drug Targets, 2006, 5(4): 453–79.
[7] Tache Y M, WangL, et al. CRF1 receptor signaling path-ways are involved in stress-related alterations of colonic function and viscerosensitivity: imp lications for irritable bowel syndrome [J]. B r J Pharm acol, 2004, 141 (8):1321-30.
[8] PorcherC J, PeinnequinA, et al. Expression and effects of metabotrop ic CRF1 and CRF2 recep tors in rat small intestine [J]. Physiol Gastrointest L iver Physiol, 2005, 88 (5):G109121103.
[9] Karteris E GA, Kouma nta kis E , et al. Reduced Exp ression of CR H-R1αin human preeclamptic and IU GR placenta [J]. J Clin Endocrinol &Metab, 2003, 88:1363-70.
[10] Grazia ni G FrnG, Pozzoli G , et al. Corticot ropin- releasing hormone receptor-1 in human endomet rial cancer [J]. Oncol Rep, 2006, 15 (2):375-9.
[11] Hauger RL, Risbrough V, Brauns O, Dautzenberg FM. Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets [J]. CNS Neurol Disord Drug Targets, 2006, 5(4):453-79.
[12] Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM, Gold LH, et al. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development [J]. Neuron, 1998, 20(6):1093-102.
[13] Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK, et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotrophin -releasing hormone receptor 1 [J]. Nat Genet, 1998, 19(2):162-6.
[14] Assil IQ, Qi LJ, Arai M, Shomali M, Abou-Samra AB. Juxtamembrane region of the amino terminus of the corticotropin releasing factor receptor type 1 is important for ligand interaction [J]. Biochemistry, 2001, 40(5):1187-95.
[15] Thomson F, Craighead M. Innovative approaches for the treatment of depression: targeting the HPA axis [J]. Neurochem Res, 2008, 33(4):691-707.
[16] Marcus Ising* HEKn, Elisabeth B. Binder, Thomas Nickel,, Sieglinde Modell FH. The combined dexamethasone/CRH test as a potential surrogate marker in depression [J]. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2005, 29:1085– 93.
[17] Florian Holsboer MD, Ph.D. The Corticosteroid Receptor Hypothesis of Depre -ssion [J]. Neuropsychopharmacology 2000, 23:477-501.
[18] Steckler T HF. Corticotropin-releasing hormone receptor subtypes and emotion. [J]. Biol Psychiatry, 1999, 46(11):1480-508.
[19] Orozco-Cabal L, Pollandt S, Liu J, Shinnick-Gallagher P, Gallagher JP. Regulation of synaptic transmission by CRF receptors [J]. Rev Neurosci, 2006, 17(3):279-307.
[20] Chalmers DT, Lovenberg TW, De Souza EB. Localization of novel corticotrophin -releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression [J]. J Neurosci, 1995, 15(10):6340-50.
[21] McEwen BS. Mood disorders and allostatic load [J]. Biol Psychiatry, 2003, 54(3):200-7.
[22] Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications [J]. Psychopharmacology (Berl), 2004, 174(1):151-62.
[23] Chen Y, Bender RA, Brunson KL, Pomper JK, Grigoriadis DE, Wurst W, et al. Modulation of dendritic differentiation by corticotropin-releasing factor in the developing hippocampus [J]. Proc Natl Acad Sci U S A, 2004, 101(44):15782-7.
[24] Elevated concentrations of CSF corticotropin-releasing factor-like immunoreac -tivity in depressed patients [J]. Science, 1984 Dec 14, 226(4680):1342-4.
[25] Marcelo Paez-Pereda FHFH. Corticotropin releasing factor eceptor antagonists for major depressive disorder [J]. Expert Opin Investig Drugs, 2011, 20(4):519-35.
[26] Peter Timpl1 RS, Inge Sillaber1, Adelheid Kresse1, Johannes M.H.M. Reul1, Günter K. Stalla1, Veronique Blanquet1, Thomas Steckler1, Florian Holsboer1 & Wolfgang Wurst1,2. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1 [J]. nature genetics, 1998, 19.
[27] Steckler T DF. Corticotropin-releasing factor receptor antagonists in affective disorders and drug dependence - an update. [J]. CNS Neurol Disord Drug Targets,2006, 5(2):147-65.
[28] George W. Smith kJ-MA, Francoise Dellu AC, Louise M. Bilezikjian LHG, Ruoping Chen YM, Chris Hauser CAB, Paul E. Sawchenko GFK, Wylie Vale, and Kuo-Fen Lee. Corticotropin Releasing Factor Receptor 1–Deficient Mice Display Decreased Anxiety, Impaired Stress Response, and Aberrant Neuroendocrine Development [J]. Neuron, June, 1998, 20:1093–102.
[29] Nielsen DM. Corticotropin-releasing factor type-1 receptor antagonists: The next class of antidepressants? [J]. Life Sciences, 2006, 78:909– 19.
[30] Nielsen DM. Corticotropin-releasing factor type-1 receptor antagonists: the next class of antidepressants? [J]. Life Sci, 2006, 78(9):909-19.
[31] Gross RS GZ, Dyck B, Coon T, Huang CQ, Lowe RF, Marinkovic D, Moorjani M, Nelson J, Zamani-Kord S, Grigoriadis DE, Hoare SR, Crowe PD, Bu JH, Haddach M, McCarthy J, Saunders J, Sullivan R, Chen T, Williams JP. Design and synthesis of tricyclic corticotropin-releasing factor-1 antagonists [J]. J Med Chem, 2005, 48(18):5780-93.
[32] McCarthy JR, Heinrichs SC, Grigoriadis DE. Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications [J]. Curr Pharm Des, 1999, 5(5):289-315.
[33] Ising M, Holsboer F. CRH1 Receptor Antagonists for the Treatment of Depression and Anxiety [J]. Experimental and Clinical Psychopharmacology 2007:519–28.
[34] Ising M, Zimmermann US, Kunzel HE, Uhr M, Foster AC, Learned-Coughlin SM, et al. High-affinity CRF1 receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response [J]. Neuropsychopharmacology, 2007, 32(9):1941-9.
[35] Heike E. Ku¨nzel AWZ, Thomas Nickel, Nibal Ackl, Manfred Uhr,, Annette Sonntag MI, Florian Holsboer. Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects [J]. Psychiatric Research, 2003, 37: 525–33.
[36] Masayuki UCHIDA MS, and Kimiko SHIMIZU. Effects of Urocortin, Corticotropin-Releasing Factor (CRF) Receptor Agonist, and Astressin, CRF Receptor Antagonist, on the Sleep–Wake Pattern: Analysis by Radiotelemetry in Conscious Rats [J]. Biol Pharm Bull, 2007, 30(10):1895-7.
[37] George Zislis TVD, Melissa Prado, Hina P. Shah, M.D., and Adrie W. Bruijnzeel, Ph.D. Effects of the CRF receptor antagonist D-Phe CRF(12-41) and theα2-adrenergic receptor agonist clonidine on stress-induced reinstatement of nicotine-seeking behavior in rats [J]. Neuropharmacology 2007 December, 53(8):958–66.
[38] McGregor DP. Discovering and improving novel peptide therapeutics [J]. CurrentOpinion in Pharmacology, 2008, 8:616–9.
[39] Noppe W, Plieva F, Galaev IY, Pottel H, Deckmyn H, Mattiasson B. Chromato -panning: an efficient new mode of identifying suitable ligands from phage display libraries [J]. BMC Biotechnol, 2009, 9:21.
[40] Li M. Applications of display technology in protein analysis [J]. Nat Biotechnol, 2000, 18(12):1251-6.
[41] Sam R. J. Hoare SKS, David A. Schwarz, Nicholas Ling, Wylie W. Vale, Paul D. Crowe, and Dimitri E. Grigoriadis. Ligand Affinity for Amino-Terminal and Juxtamembrane Domains of the Corticotropin Releasing Factor Type I Receptor: Regulation by G-Protein and Nonpeptide Antagonists [J]. Biochemistry, 2004, 43 (13): 3996–4011.
[42] CARRIOM M VA. Construction and deconstruction of bacterial inclusion bodies [J]. J Biotechnol, 2002, 96:3- 12.
[43] HOFFMANN F VDHJ, ZIDEK N. Minimizing inclusion body formation during recombinant protein production in Escherichia coli at bench and pilot plant scale [J]. EnzymeMicrobTechnol, 2004, 34:235- 41.
[44] Pande J, Szewczyk MM, Grover AK. Phage display: concept, innovations, applications and future [J]. Biotechnol Adv, 28(6):849-58.
[45] Adda CG, Anders RF, Tilley L, Foley M. Random sequence libraries displayed on phage: identification of biologically important molecules [J]. Comb Chem High Throughput Screen, 2002, 5(1):1-14.
[46] Richard L. Hauger, Victoria Risbrough, Olaf Brauns, and Frank M. Dautzenberg. Corticotropin Releasing Factor (CRF) Receptor Signaling in the Central Nervous System: New Molecular Targets [J]. CNS Neurol Disord Drug Targets, 2006, 5(4):453–79.
[47] Wille S, Sydow S, Palchaudhuri MR, Spiess J, Dautzenberg FM. Identification of amino acids in the N-terminal domain of corticotropin-releasing factor receptor 1 that are important determinants of high-affinity ligand binding [J]. J Neurochem, 1999, 72(1):388-95.
[48] Perrin MH, Fischer WH, Kunitake KS, Craig AG, Koerber SC, Cervini LA, et al. Expression, purification, and characterization of a soluble form of the first extracellular domain of the human type 1 corticotropin releasing factor receptor [J]. J Biol Chem, 2001, 276(34):31528-34.
[49] Perrin MH, DiGruccio MR, Koerber SC, Rivier JE, Kunitake KS, Bain DL, et al. A soluble form of the first extracellular domain of mouse type 2beta corticotropin-releasing factor receptor reveals differential ligand specificity [J]. J Biol Chem, 2003, 278(18):15595-600.
[50] Dautzenberg FM, Kilpatrick GJ, Wille S, Hauger RL. The ligand-selective domainsof corticotropin-releasing factor type 1 and type 2 receptor reside in different extracellular domains: generation of chimeric receptors with a novel ligand -selective profile [J]. J Neurochem, 1999, 73(2):821-9.
[51] Dautzenberg FM, Wille S, Lohmann R, Spiess J. Mapping of the ligand-selective domain of the Xenopus laevis corticotropin-releasing factor receptor 1: implications for the ligand-binding site [J]. Proc Natl Acad Sci U S A, 1998, 95(9):4941-6.
[52] Dautzenberg FM, Wille S. Binding differences of human and amphibian corticotropin-releasing factor type 1 (CRF(1)) receptors: identification of amino acids mediating high-affinity astressin binding and functional antagonism [J]. Regul Pept, 2004, 118(3):165-73.
[53] Hoare SR, Sullivan SK, Fan J, Khongsaly K, Grigoriadis DE. Peptide ligand binding properties of the corticotropin-releasing factor (CRF) type 2 receptor: pharmacology of endogenously expressed receptors, G-protein-coupling sensitivity and determinants of CRF2 receptor selectivity [J]. Peptides, 2005, 26(3):457-70.
[54] Liaw CW, Grigoriadis DE, Lorang MT, De Souza EB, Maki RA. Localization of agonist- and antagonist-binding domains of human corticotropin-releasing factor receptors [J]. Mol Endocrinol, 1997, 11(13):2048-53.
[55] Liaw CW, Grigoriadis DE, Lovenberg TW, De Souza EB, Maki RA. Localization of ligand-binding domains of human corticotropin-releasing factor receptor: a chimeric receptor approach [J]. Mol Endocrinol, 1997, 11(7):980-5.
[56] Perrin MH, Sutton S, Bain DL, Berggren WT, Vale WW. The first extracellular domain of corticotropin releasing factor-R1 contains major binding determinants for urocortin and astressin [J]. Endocrinology, 1998, 139(2):566-70.
[57] Nielsen SM, Nielsen LZ, Hjorth SA, Perrin MH, Vale WW. Constitutive activation of tethered-peptide/corticotropin-releasing factor receptor chimeras [J]. Proc Natl Acad Sci U S A, 2000, 97(18):10277-81.
[58] Hoare SR, Sullivan SK, Ling N, Crowe PD, Grigoriadis DE. Mechanism of corticotropin -releasing factor type I receptor regulation by nonpeptide antagonists [J]. Mol Pharmacol, 2003, 63(3):751-65.
[59] Grigoriadis DE. Expert Opin TherTargets [J]. 2005, 9:651–84.
[60] Hoare SR, Sullivan SK, Pahuja A, Ling N, Crowe PD, Grigoriadis DE. Conformational states of the corticotropin releasing factor 1 (CRF1) receptor: detection, and pharmacological evaluation by peptide ligands [J]. Peptides, 2003, 24(12):1881-97.
[61] Hauger RL, Grigoriadis DE, Dallman MF, Plotsky PM, Vale WW, Dautzenberg FM. International Union of Pharmacology. XXXVI. Current status of the nomenclature for receptors for corticotropin-releasing factor and their ligands [J].Pharmacol Rev, 2003, 55(1):21-6.
[62] Olaf Brauns SB, Bodo Zimmermann, Olaf Jahn, Joachim Spiess. Differential responsiveness of CRF receptor subtypes to N-terminal truncation of peptidic ligands [J]. Peptides 2002, 23:881–8.
[63] H Berger NH, D Wietfeld, M Bienert and M Beyermann. Evidence that corticotropin-releasing factor receptor type 1 couples to Gs- and Gi-proteins through different conformations of its J-domain [J]. British Journal of Pharmacology, 2006, 149:942–7.
[1] WHO Media centre, Mental and neurological disorders, Fact sheet N 265, [J]. 2001.
[2] Jacobi F, Wittchen HU, Holting C, Hofler M, Pfister H, Muller N, et al. Prevalence, co-morbidity and correlates of mental disorders in the general population: results from the German Health Interview and Examination Survey (GHS) [J]. Psychol Med, 2004, 34(4):597-611.
[3] Kessler RC. Epidemiology of women and depression [J]. J Affect Disord, 2003, 74(1):5-13.
[4] Murray C LA. Summary: the global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Harvard School of Public Health on behalf of the World Health Organization and the World Bank. Harvard University Press, Cambridge; [J]. 1996.
[5] Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice [J]. Am J Psychiatry, 2006, 163(1):28-40.
[6] Kroenke K, West SL, Swindle R, Gilsenan A, Eckert GJ, Dolor R, et al. Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: a randomized trial [J]. Jama, 2001, 286(23):2947-55.
[7] Luo L, Rodriguez E, Jerbi K, Lachaux JP, Martinerie J, Corbetta M, et al. Ten years of Nature Reviews Neuroscience: insights from the highly cited [J]. Nat Rev Neurosci, 11(10):718-26.
[8] Uhr M, Tontsch A, Namendorf C, Ripke S, Lucae S, Ising M, et al. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression [J]. Neuron, 2008, 57(2):203-9.
[9] van Rossum EF, Binder EB, Majer M, Koper JW, Ising M, Modell S, et al. Polymorphisms of the glucocorticoid receptor gene and major depression [J]. Biol Psychiatry, 2006, 59(8):681-8.
[10] Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B, et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment [J]. Nat Genet, 2004, 36(12):1319-25.
[11] Francis DD, Caldji C, Champagne F, Plotsky PM, Meaney MJ. The role of corticotropin-releasing factor--norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses tostress [J]. Biol Psychiatry, 1999, 46(9):1153-66.
[12] Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB. The link between childhood trauma and depression: insights from HPA axis studies in humans [J]. Psychoneuroendocrinology, 2008, 33(6):693-710.
[13] Holsboer F. The corticosteroid receptor hypothesis of depression [J]. Neuropsycho -pharmacology, 2000, 23(5):477-501.
[14] Pacher P, Kohegyi E, Kecskemeti V, Furst S. Current trends in the development of new antidepressants [J]. Curr Med Chem, 2001, 8(2):89-100.
[15] Shelton RC. The dual-action hypothesis: does pharmacology matter? [J]. J Clin Psychiatry, 2004, 65 Suppl 17:5-10.
[16] Holsboer F. The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety [J]. J Psychiatr Res, 1999, 33(3):181-214.
[17] Schmidt MV, Trumbach D, Weber P, Wagner K, Scharf SH, Liebl C, et al. Individual stress vulnerability is predicted by short-term memory and AMPA receptor subunit ratio in the hippocampus [J]. J Neurosci, 30(50):16949-58.
[18] Rivier J, Spiess J, Vale W. Characterization of rat hypothalamic corticotrophin -releasing factor [J]. Proc Natl Acad Sci U S A, 1983, 80(15):4851-5.
[19] Smith SM VW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. [J]. Dialogues Clin Neurosci 2006, 8:383-95.
[20] Thomson F, Craighead M. Innovative approaches for the treatment of depression: targeting the HPA axis [J]. Neurochem Res, 2008, 33(4):691-707.
[21] Gray TS. Amygdaloid CRF pathways. Role in autonomic, neuroendocrine, and behavioral responses to stress [J]. Ann N Y Acad Sci, 1993, 697:53-60.
[22] Lehnert H, Schulz C, Dieterich K. Physiological and neurochemical aspects of corticotropin-releasing factor actions in the brain: the role of the locus coeruleus [J]. Neurochem Res, 1998, 23(8):1039-52.
[23] Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB. The role of corticotrophin -releasing factor in depression and anxiety disorders [J]. J Endocrinol, 1999, 160(1):1-12.
[24] Ising M, Kunzel HE, Binder EB, Nickel T, Modell S, Holsboer F. The combined dexamethasone/CRH test as a potential surrogate marker in depression [J]. Prog Neuropsychopharmacol Biol Psychiatry, 2005, 29(6):1085-93.
[25] Pariante CM, Miller AH. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment [J]. Biol Psychiatry, 2001, 49(5):391-404.
[26] Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders [J]. Am J Psychiatry, 2003, 160(9):1554-65.
[27] Holsboer F, Muller OA, Doerr HG, Sippell WG, Stalla GK, Gerken A, et al. ACTH and multisteroid responses to corticotropin-releasing factor in depressive illness: relationship to multisteroid responses after ACTH stimulation and dexamethasone suppression [J]. Psychoneuroendocrinology, 1984, 9(2):147-60.
[28] Gold PW, Chrousos G, Kellner C, Post R, Roy A, Augerinos P, et al. Psychiatric implications of basic and clinical studies with corticotropin-releasing factor [J]. Am J Psychiatry, 1984, 141(5):619-27.
[29] Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K, et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreac -tivity in depressed patients [J]. Science, 1984, 226(4680):1342-4.
[30] Nemeroff CB, Owens MJ, Bissette G, Andorn AC, Stanley M. Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims [J]. Arch Gen Psychiatry, 1988, 45(6):577-9.
[31] Hartline KM, Owens MJ, Nemeroff CB. Postmortem and cerebrospinal fluid studies of corticotropin-releasing factor in humans [J]. Ann N Y Acad Sci, 1996, 780:96-105.
[32] Heuser I, Bissette G, Dettling M, Schweiger U, Gotthardt U, Schmider J, et al. Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: response to amitriptyline treatment [J]. Depress Anxiety, 1998, 8(2):71-9.
[33] Merali Z, Du L, Hrdina P, Palkovits M, Faludi G, Poulter MO, et al. Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region [J]. J Neurosci, 2004, 24(6):1478-85.
[34] Raadsheer FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothala -mic paraventricular nucleus of depressed patients [J]. Neuroendocrin -ology, 1994, 60(4):436-44.
[35] Holsboer F, Ising M. Stress hormone regulation: biological role and translation into therapy [J]. Annu Rev Psychol, 61:81-109, C1-11.
[36] Holsboer F. Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy [J]. J Affect Disord, 2001, 62(1-2):77-91.
[37] Nemeroff CB, Bissette G, Akil H, Fink M. Neuropeptide concentrations in the cerebrospinal fluid of depressed patients treated with electroconvulsive therapy. Corticotrophin-releasing factor, beta-endorphin and somatostatin [J]. Br J Psychiatry, 1991, 158:59-63.
[38] Holsboer F, Liebl R, Hofschuster E. Repeated dexamethasone suppression test during depressive illness. Normalisation of test result compared with clinicalimprovement [J]. J Affect Disord, 1982, 4(2):93-101.
[39] Ising M, Horstmann S, Kloiber S, Lucae S, Binder EB, Kern N, et al. Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression - a potential biomarker? [J]. Biol Psychiatry, 2007, 62(1):47-54.
[40] Reul JM, Stec I, Soder M, Holsboer F. Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary -adrenocortical system [J]. Endocrinology, 1993, 133(1):312-20.
[41] de Kloet ER, Sibug RM, Helmerhorst FM, Schmidt MV. Stress, genes and the mechanism of programming the brain for later life [J]. Neurosci Biobehav Rev, 2005, 29(2):271-81.
[42] Orozco-Cabal L, Pollandt S, Liu J, Shinnick-Gallagher P, Gallagher JP. Regulation of synaptic transmission by CRF receptors [J]. Rev Neurosci, 2006, 17(3):279-307.
[43] Chalmers DT, Lovenberg TW, De Souza EB. Localization of novel corticotrophin -releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression [J]. J Neurosci, 1995, 15(10):6340-50.
[44] McEwen BS. Mood disorders and allostatic load [J]. Biol Psychiatry, 2003, 54(3):200-7.
[45] Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications [J]. Psychopharmacology (Berl), 2004, 174(1):151-62.
[46] Chen Y, Bender RA, Brunson KL, Pomper JK, Grigoriadis DE, Wurst W, et al. Modulation of dendritic differentiation by corticotropin-releasing factor in the developing hippocampus [J]. Proc Natl Acad Sci U S A, 2004, 101(44):15782-7.
[47] Lewis K, Li C, Perrin MH, Blount A, Kunitake K, Donaldson C, et al. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor [J]. Proc Natl Acad Sci U S A, 2001, 98(13):7570-5.
[48] Hsu SY, Hsueh AJ. Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor [J]. Nat Med, 2001, 7(5):605-11.
[49] Reyes TM, Lewis K, Perrin MH, Kunitake KS, Vaughan J, Arias CA, et al. Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors [J]. Proc Natl Acad Sci U S A, 2001, 98(5):2843-8.
[50] Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin [J]. Science, 1981, 213(4514):1394-7.
[51] Perrin MH, Donaldson CJ, Chen R, Lewis KA, Vale WW. Cloning and functional expression of a rat brain corticotropin releasing factor (CRF) receptor [J]. Endocrinology, 1993, 133(6):3058-61.
[52] Chen R, Lewis KA, Perrin MH, Vale WW. Expression cloning of a human corticotropin-releasing-factor receptor [J]. Proc Natl Acad Sci U S A, 1993, 90(19):8967-71.
[53] Vamvakopoulos NC, Sioutopoulou TO. Human corticotropin-releasing hormone receptor gene (CRHR) is located on the long arm of chromosome 17 (17q12-qter) [J]. Chromosome Res, 1994, 2(6):471-3.
[54] Polymeropoulos MH, Torres R, Yanovski JA, Chandrasekharappa SC, Ledbetter DH. The human corticotropin-releasing factor receptor (CRHR) gene maps to chromosome 17q12-q22 [J]. Genomics, 1995, 28(1):123-4.
[55] Chang CP, Pearse RV, 2nd, O'Connell S, Rosenfeld MG. Identification of a seven transmembrane helix receptor for corticotropin-releasing factor and sauvagine in mammalian brain [J]. Neuron, 1993, 11(6):1187-95.
[56] Vita N, Laurent P, Lefort S, Chalon P, Lelias JM, Kaghad M, et al. Primary structure and functional expression of mouse pituitary and human brain corticotrophin releasing factor receptors [J]. FEBS Lett, 1993, 335(1):1-5.
[57] Yu J, Xie LY, Abou-Samra AB. Molecular cloning of a type A chicken corticotropin-releasing factor receptor with high affinity for urotensin I [J]. Endocrinology, 1996, 137(1):192-7.
[58] Dautzenberg FM, Dietrich K, Palchaudhuri MR, Spiess J. Identification of two corticotropin-releasing factor receptors from Xenopus laevis with high ligand selectivity: unusual pharmacology of the type 1 receptor [J]. J Neurochem, 1997, 69(4):1640-9.
[59] Myers DA, Trinh JV, Myers TR. Structure and function of the ovine type 1 corticotropin releasing factor receptor (CRF1) and a carboxyl-terminal variant [J]. Mol Cell Endocrinol, 1998, 144(1-2):21-35.
[60] Ross PC, Kostas CM, Ramabhadran TV. A variant of the human corticotrophin -releasing factor (CRF) receptor: cloning, expression and pharmacology [J]. Biochem Biophys Res Commun, 1994, 205(3):1836-42.
[61] Grammatopoulos DK, Dai Y, Randeva HS, Levine MA, Karteris E, Easton AJ, et al. A novel spliced variant of the type 1 corticotropin-releasing hormone receptor with a deletion in the seventh transmembrane domain present in the human pregnant term myometrium and fetal membranes [J]. Mol Endocrinol, 1999, 13(12): 2189-202.
[62] Hoare SR, Sullivan SK, Pahuja A, Ling N, Crowe PD, Grigoriadis DE. Conformational states of the corticotropin releasing factor 1 (CRF1) receptor:detection, and pharmacological evaluation by peptide ligands [J]. Peptides, 2003, 24(12):1881-97.
[63] Hoare SR. Mechanisms of peptide and nonpeptide ligand binding to Class B G-protein-coupled receptors [J]. Drug Discov Today, 2005, 10(6):417-27.
[64] Grigoriadis DE, Hoare SR, Lechner SM, Slee DH, Williams JA. Drugability of extracellular targets: discovery of small molecule drugs targeting allosteric, functional, and subunit-selective sites on GPCRs and ion channels [J]. Neuropsychopharmacology, 2009, 34(1):106-25.
[65] Lederis K, Letter A, McMaster D, Moore G, Schlesinger D. Complete amino acid sequence of urotensin I, a hypotensive and corticotropin-releasing neuropeptide from Catostomus [J]. Science, 1982, 218(4568):162-5.
[66] Montecucchi PC, Anastasi A, de Castiglione R, Erspamer V. Isolation and amino acid composition of sauvagine. An active polypeptide from methanol extracts of the skin of the South American frog Phyllomedusa sauvagei [J]. Int J Pept Protein Res, 1980, 16(3):191-9.
[67] De Souza EB, Perrin MH, Rivier J, Vale WW, Kuhar MJ. Corticotropin-releasing factor receptors in rat pituitary gland: autoradiographic localization [J]. Brain Res, 1984, 296(1):202-7.
[68] Potter E, Sutton S, Donaldson C, Chen R, Perrin M, Lewis K, et al. Distribution of corticotropin-releasing factor receptor mRNA expression in the rat brain and pituitary [J]. Proc Natl Acad Sci U S A, 1994, 91(19):8777-81.
[69] De Souza EB, Insel TR, Perrin MH, Rivier J, Vale WW, Kuhar MJ. Corticotrophin -releasing factor receptors are widely distributed within the rat central nervous system: an autoradiographic study [J]. J Neurosci, 1985, 5(12):3189-203.
[70] Reul JM, Holsboer F. Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression [J]. Curr Opin Pharmacol, 2002, 2(1):23-33.
[71] Gehlert DR, Shekhar A, Morin SM, Hipskind PA, Zink C, Gackenheimer SL, et al. Stress and central Urocortin increase anxiety-like behavior in the social interaction test via the CRF1 receptor [J]. Eur J Pharmacol, 2005, 509(2-3): 145-53.
[72] Coste SC, Murray SE, Stenzel-Poore MP. Animal models of CRH excess and CRH receptor deficiency display altered adaptations to stress [J]. Peptides, 2001, 22(5):733-41.
[73] Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM, Gold LH, et al. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development [J]. Neuron, 1998, 20(6):1093-102.
[74] Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK, et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotrophin-releasing hormone receptor 1 [J]. Nat Genet, 1998, 19(2):162-6.
[75] Muller MB, Zimmermann S, Sillaber I, Hagemeyer TP, Deussing JM, Timpl P, et al. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress [J]. Nat Neurosci, 2003, 6(10):1100-7.
[76] Coric V, Feldman HH, Oren DA, Shekhar A, Pultz J, Dockens RC, et al. Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder [J]. Depress Anxiety, 27(5):417-25.
[77] Sweetser S, Camilleri M, Linker Nord SJ, Burton DD, Castenada L, Croop R, et al. Do corticotropin releasing factor-1 receptors influence colonic transit and bowel function in women with irritable bowel syndrome? [J]. Am J Physiol Gastrointest Liver Physiol, 2009, 296(6):G1299-306.
[78] Tojo K, Abou-Samra AB. Corticotropin-releasing factor (CRF) stimulates 45Ca2+ uptake in the mouse corticotroph cell line AtT-20 [J]. Life Sci, 1993, 52(7):621-30.
[79] Kovalovsky D, Refojo D, Liberman AC, Hochbaum D, Pereda MP, Coso OA, et al. Activation and induction of NUR77/NURR1 in corticotrophs by CRH/cAMP: involvement of calcium, protein kinase A, and MAPK pathways [J]. Mol Endocrinol, 2002, 16(7):1638-51.
[80] Hoare SR, Sullivan SK, Schwarz DA, Ling N, Vale WW, Crowe PD, et al. Ligand affinity for amino-terminal and juxtamembrane domains of the corticotropin releasing factor type I receptor: regulation by G-protein and nonpeptide antagonists [J]. Biochemistry, 2004, 43(13):3996-4011.
[81] Hoare SR, Brown BT, Santos MA, Malany S, Betz SF, Grigoriadis DE. Single amino acid residue determinants of non-peptide antagonist binding to the corticotropin-releasing factor1 (CRF1) receptor [J]. Biochem Pharmacol, 2006, 72(2):244-55.
[82] Liaw CW, Grigoriadis DE, Lovenberg TW, De Souza EB, Maki RA. Localization of ligand-binding domains of human corticotropin-releasing factor receptor: a chimeric receptor approach [J]. Mol Endocrinol, 1997, 11(7):980-5.
[83] Hoare SR, Fleck BA, Gross RS, Crowe PD, Williams JP, Grigoriadis DE. Allosteric ligands for the corticotropin releasing factor type 1 receptor modulate conformational states involved in receptor activation [J]. Mol Pharmacol, 2008, 73(5):1371-80.
[84] McCarthy JR, Heinrichs SC, Grigoriadis DE. Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications [J]. Curr Pharm Des, 1999, 5(5):289-315.
[85] Gross RS, Guo Z, Dyck B, Coon T, Huang CQ, Lowe RF, et al. Design and synthesis of tricyclic corticotropin-releasing factor-1 antagonists [J]. J Med Chem,2005, 48(18):5780-93.
[86] Saunders J, Williams J. Antagonists of the corticotropin releasing factor receptor [J]. Prog Med Chem, 2003, 41:195-247.
[87] Steckler T, Dautzenberg FM. Corticotropin-releasing factor receptor antagonists in affective disorders and drug dependence-- an update [J]. CNS Neurol Disord Drug Targets, 2006, 5(2):147-65.
[88] Valdez GR. Development of CRF1 receptor antagonists as antidepressants and anxiolytics: progress to date [J]. CNS Drugs, 2006, 20(11):887-96.
[89] Zorrilla EP, Koob GF. The therapeutic potential of CRF1 antagonists for anxiety [J]. Expert Opin Investig Drugs, 2004, 13(7):799-828.
[90] Kehne JH, Cain CK. Therapeutic utility of non-peptidic CRF1 receptor antagonists in anxiety, depression, and stress-related disorders: evidence from animal models [J]. Pharmacol Ther, 128(3):460-87.
[91] Grigoriadis DE. The corticotropin-releasing factor receptor: a novel target for the treatment of depression and anxiety-related disorders [J]. Expert Opin Ther Targets, 2005, 9(4):651-84.
[92] Tellew JE, Luo Z. Small molecule antagonists of the corticotropin releasing factor (CRF) receptor: recent medicinal chemistry developments [J]. Curr Top Med Chem, 2008, 8(6):506-20.
[93] Hemley CF, McCluskey A, Keller PA. Corticotropin releasing hormone--a GPCR drug target [J]. Curr Drug Targets, 2007, 8(1):105-15.
[94] Zorrilla EP, Koob GF. Progress in corticotropin-releasing factor-1 antagonist development [J]. Drug Discov Today, 15(9-10):371-83.
[95] Chen C, Wilcoxen KM, Huang CQ, Xie YF, McCarthy JR, Webb TR, et al. Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1, 5-a]py rimidine (NBI 30775/R121919) and structure--activity relationships of a series of potent and orally active corticotropin-releasing factor receptor antagonists [J]. J Med Chem, 2004, 47(19):4787-98.
[96] Heinrichs SC, De Souza EB, Schulteis G, Lapsansky JL, Grigoriadis DE. Brain penetrance, receptor occupancy and antistress in vivo efficacy of a small molecule corticotropin releasing factor type I receptor selective antagonist [J]. Neuropsycho -pharmacology, 2002, 27(2):194-202.
[97] Held K, Kunzel H, Ising M, Schmid DA, Zobel A, Murck H, et al. Treatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression [J]. J Psychiatr Res, 2004, 38(2):129-36.
[98] Kunzel HE, Zobel AW, Nickel T, Ackl N, Uhr M, Sonntag A, et al. Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects [J]. J Psychiatr Res, 2003, 37(6):525-33.
[99] Kunzel HE, Ising M, Zobel AW, Nickel T, Ackl N, Sonntag A, et al. Treatment with a CRH-1-receptor antagonist (R121919) does not affect weight or plasma leptin concentration in patients with major depression [J]. J Psychiatr Res, 2005, 39(2):173-7.
[100] Zobel AW, Nickel T, Kunzel HE, Ackl N, Sonntag A, Ising M, et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated [J]. J Psychiatr Res, 2000, 34(3):171-81.
[101] Hamilton M. Rating depressive patients [J]. J Clin Psychiatry, 1980, 41(12 Pt 2):21-4.
[102] Kimura M, Muller-Preuss P, Lu A, Wiesner E, Flachskamm C, Wurst W, et al. Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep [J]. Mol Psychiatry, 15(2):154-65.
[103] Holsboer F, von Bardeleben U, Steiger A. Effects of intravenous corticotrophin -releasing hormone upon sleep-related growth hormone surge and sleep EEG in man [J]. Neuroendocrinology, 1988, 48(1):32-8.
[104] Chen YL, Braselton J, Forman J, Gallaschun RJ, Mansbach R, Schmidt AW, et al. Synthesis and SAR of 2-aryloxy-4-alkoxy-pyridines as potent orally active corticotropin-releasing factor 1 receptor antagonists [J]. J Med Chem, 2008, 51(5):1377-84.
[105] Binneman B, Feltner D, Kolluri S, Shi Y, Qiu R, Stiger T. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression [J]. Am J Psychiatry, 2008, 165(5):617-20.
[106] Gilligan PJ, He L, Clarke T, Tivitmahaisoon P, Lelas S, Li YW, et al. 8-(4- Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: selective and centrally active corticotropin-releasing factor receptor-1 (CRF1) antagonists [J]. J Med Chem, 2009, 52(9):3073-83.
[107] Di Fabio R, St-Denis Y, Sabbatini FM, Andreotti D, Arban R, Bernasconi G, et al. Synthesis and pharmacological characterization of novel druglike corticotrophin -releasing factor 1 antagonists [J]. J Med Chem, 2008, 51(23):7370-9.
[108] Tellew JE, Lanier M, Moorjani M, Lin E, Luo Z, Slee DH, et al. Discovery of NBI-77860/GSK561679, a potent corticotropin-releasing factor (CRF1) receptor antagonist with improved pharmacokinetic properties [J]. Bioorg Med Chem Lett, 20(24):7259-64.
[109] Lu A, Steiner MA, Whittle N, Vogl AM, Walser SM, Ableitner M, et al. Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior [J]. Mol Psychiatry, 2008, 13(11): 1028-42.
[110] Licinio J, O'Kirwan F, Irizarry K, Merriman B, Thakur S, Jepson R, et al. Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans [J]. Mol Psychiatry, 2004, 9(12):1075-82.
[111] Lekman M, Laje G, Charney D, Rush AJ, Wilson AF, Sorant AJ, et al. The FKBP5-gene in depression and treatment response--an association study in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Cohort [J]. Biol Psychiatry, 2008, 63(12):1103-10.
[112] Kirchheiner J, Lorch R, Lebedeva E, Seeringer A, Roots I, Sasse J, et al. Genetic variants in FKBP5 affecting response to antidepressant drug treatment [J]. Pharmacogenomics, 2008, 9(7):841-6.
[113] Horstmann S, Lucae S, Menke A, Hennings JM, Ising M, Roeske D, et al. Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment [J]. Neuropsychopharmacology, 35(3):727-40.
[114] Scammell JG, Denny WB, Valentine DL, Smith DF. Overexpression of the FK506-binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three New World primates [J]. Gen Comp Endocrinol, 2001, 124(2):152-65.
[115] Vermeer H, Hendriks-Stegeman BI, van der Burg B, van Buul-Offers SC, Jansen M. Glucocorticoid-induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression: a potential marker for glucocorticoid sensitivity, potency, and bioavailability [J]. J Clin Endocrinol Metab, 2003, 88(1):277-84.
[116] Mennigen JA, Harris EA, Chang JP, Moon TW, Trudeau VL. Fluoxetine affects weight gain and expression of feeding peptides in the female goldfish brain [J]. Regul Pept, 2009, 155(1-3):99-104.
[117] Liu Z, Zhu F, Wang G, Xiao Z, Tang J, Liu W, et al. Association study of corticotropin-releasing hormone receptor1 gene polymorphisms and antidepressa -nt response in major depressive disorders [J]. Neurosci Lett, 2007, 414(2):155-8.
[118] Keck ME, Welt T, Wigger A, Renner U, Engelmann M, Holsboer F, et al. The anxiolytic effect of the CRH(1) receptor antagonist R121919 depends on innate emotionality in rats [J]. Eur J Neurosci, 2001, 13(2):373-80.
[119] Li YW, Hill G, Wong H, Kelly N, Ward K, Pierdomenico M, et al. Receptor occupancy of nonpeptide corticotropin-releasing factor 1 antagonist DMP696: correlation with drug exposure and anxiolytic efficacy [J]. J Pharmacol Exp Ther, 2003, 305(1):86-96.
[120] Gutman DA, Owens MJ, Skelton KH, Thrivikraman KV, Nemeroff CB. The corticotropin-releasing factor1 receptor antagonist R121919 attenuates thebehavioral and endocrine responses to stress [J]. J Pharmacol Exp Ther, 2003, 304(2):874-80.
[121] Gutman DA, Owens MJ, Thrivikraman KV, Nemeroff CB. Persistent anxiolytic affects after chronic administration of the CRF(1) receptor antagonist R121919 in rats [J]. Neuropharmacology, 60(7-8):1135-41.
[122] Chaki S, Nakazato A, Kennis L, Nakamura M, Mackie C, Sugiura M, et al. Anxiolytic- and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450 [J]. Eur J Pharmacol, 2004, 485(1-3):145-58.
[123] Lelas S, Wong H, Li YW, Heman KL, Ward KA, Zeller KL, et al. Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyr imidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats [J]. J Pharmacol Exp Ther, 2004, 309(1):293-302.
[124] Gehlert DR, Cippitelli A, Thorsell A, Le AD, Hipskind PA, Hamdouchi C, et al. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo [1,2-b]pyridazine: a novel brain-penetrant, orally available corticotrophin -releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism [J]. J Neurosci, 2007, 27(10):2718-26.
[125] Ising M, Zimmermann US, Kunzel HE, Uhr M, Foster AC, Learned-Coughlin SM, et al. High-affinity CRF1 receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response [J]. Neuropsychopharmacology, 2007, 32(9):1941-9.
[126] Schmidt ME, Andrews RD, van der Ark P, Brown T, Mannaert E, Steckler T, et al. Dose-dependent effects of the CRF (1) receptor antagonist R317573 on regional brain activity in healthy male subjects [J]. Psychopharmacology (Berl), 208(1):109-19.
[127] Hsin LW, Webster EL, Chrousos GP, Gold PW, Eckelman WC, Contoreggi C, et al. Synthesis and biological activity of fluoro-substituted pyrrolo[2,3-d] pyrimidines: the development of potential positron emission tomography imaging agents for the corticotropin-releasing hormone type 1 receptor [J]. Bioorg Med Chem Lett, 2000, 10(8):707-10.
[128] Hsin LW, Tian X, Webster EL, Coop A, Caldwell TM, Jacobson AE, et al. CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists [J]. Bioorg Med Chem, 2002, 10(1):175-83.
[129] Martarello L, Kilts CD, Ely T, Owens MJ, Nemeroff CB, Camp M, et al. Synthesis and characterization of fluorinated and iodinated pyrrolopyrimidines as PET/SPECT ligands for the CRF1 receptor [J]. Nucl Med Biol, 2001,28(2):187-95.
[130] Kumar JS, Majo VJ, Sullivan GM, Prabhakaran J, Simpson NR, Van Heertum RL, et al. Synthesis and in vivo evaluation of [11C]SN003 as a PET ligand for CRF1 receptors [J]. Bioorg Med Chem, 2006, 14(12):4029-34.
[131] Sullivan GM, Parsey RV, Kumar JS, Arango V, Kassir SA, Huang YY, et al. PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density? [J]. Nucl Med Biol, 2007, 34(4):353-61.
[2] Dautzenberg FM, Hauger RL. The CRF peptide family and their receptors: yet more partners discovered [J]. Trends Pharmacol Sci, 2002, 23(2):71-7.
[3] Bale TL, Vale WW. CRF and CRF receptors: role in stress responsivity and other behaviors [J]. Annu Rev Pharmacol Toxicol, 2004, 44:525-57.
[4] Stephen C. Heinrichs GFK. Corticotropin-Releasing Factor in Brain: A Role in Activation, Arousal, and Affect Regulation [J]. JPET, 2004, 311:427–40.
[5] Swanson LW, Sawchenko PE, Rivier J, Vale WW. Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study [J]. Neuroendocrinology, 1983, 36(3):165-86.
[6] Hauger RL, Risbrough V, Brauns O, Dautzenberg aFM. Corticotropin Releasing Factor (CRF) Receptor Signaling in the Central Nervous System: New Molecular Targets [J]. CNS Neurol Disord Drug Targets, 2006, 5(4): 453–79.
[7] Tache Y M, WangL, et al. CRF1 receptor signaling path-ways are involved in stress-related alterations of colonic function and viscerosensitivity: imp lications for irritable bowel syndrome [J]. B r J Pharm acol, 2004, 141 (8):1321-30.
[8] PorcherC J, PeinnequinA, et al. Expression and effects of metabotrop ic CRF1 and CRF2 recep tors in rat small intestine [J]. Physiol Gastrointest L iver Physiol, 2005, 88 (5):G109121103.
[9] Karteris E GA, Kouma nta kis E , et al. Reduced Exp ression of CR H-R1αin human preeclamptic and IU GR placenta [J]. J Clin Endocrinol &Metab, 2003, 88:1363-70.
[10] Grazia ni G FrnG, Pozzoli G , et al. Corticot ropin- releasing hormone receptor-1 in human endomet rial cancer [J]. Oncol Rep, 2006, 15 (2):375-9.
[11] Hauger RL, Risbrough V, Brauns O, Dautzenberg FM. Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets [J]. CNS Neurol Disord Drug Targets, 2006, 5(4):453-79.
[12] Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM, Gold LH, et al. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development [J]. Neuron, 1998, 20(6):1093-102.
[13] Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK, et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotrophin -releasing hormone receptor 1 [J]. Nat Genet, 1998, 19(2):162-6.
[14] Assil IQ, Qi LJ, Arai M, Shomali M, Abou-Samra AB. Juxtamembrane region of the amino terminus of the corticotropin releasing factor receptor type 1 is important for ligand interaction [J]. Biochemistry, 2001, 40(5):1187-95.
[15] Thomson F, Craighead M. Innovative approaches for the treatment of depression: targeting the HPA axis [J]. Neurochem Res, 2008, 33(4):691-707.
[16] Marcus Ising* HEKn, Elisabeth B. Binder, Thomas Nickel,, Sieglinde Modell FH. The combined dexamethasone/CRH test as a potential surrogate marker in depression [J]. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2005, 29:1085– 93.
[17] Florian Holsboer MD, Ph.D. The Corticosteroid Receptor Hypothesis of Depre -ssion [J]. Neuropsychopharmacology 2000, 23:477-501.
[18] Steckler T HF. Corticotropin-releasing hormone receptor subtypes and emotion. [J]. Biol Psychiatry, 1999, 46(11):1480-508.
[19] Orozco-Cabal L, Pollandt S, Liu J, Shinnick-Gallagher P, Gallagher JP. Regulation of synaptic transmission by CRF receptors [J]. Rev Neurosci, 2006, 17(3):279-307.
[20] Chalmers DT, Lovenberg TW, De Souza EB. Localization of novel corticotrophin -releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression [J]. J Neurosci, 1995, 15(10):6340-50.
[21] McEwen BS. Mood disorders and allostatic load [J]. Biol Psychiatry, 2003, 54(3):200-7.
[22] Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications [J]. Psychopharmacology (Berl), 2004, 174(1):151-62.
[23] Chen Y, Bender RA, Brunson KL, Pomper JK, Grigoriadis DE, Wurst W, et al. Modulation of dendritic differentiation by corticotropin-releasing factor in the developing hippocampus [J]. Proc Natl Acad Sci U S A, 2004, 101(44):15782-7.
[24] Elevated concentrations of CSF corticotropin-releasing factor-like immunoreac -tivity in depressed patients [J]. Science, 1984 Dec 14, 226(4680):1342-4.
[25] Marcelo Paez-Pereda FHFH. Corticotropin releasing factor eceptor antagonists for major depressive disorder [J]. Expert Opin Investig Drugs, 2011, 20(4):519-35.
[26] Peter Timpl1 RS, Inge Sillaber1, Adelheid Kresse1, Johannes M.H.M. Reul1, Günter K. Stalla1, Veronique Blanquet1, Thomas Steckler1, Florian Holsboer1 & Wolfgang Wurst1,2. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1 [J]. nature genetics, 1998, 19.
[27] Steckler T DF. Corticotropin-releasing factor receptor antagonists in affective disorders and drug dependence - an update. [J]. CNS Neurol Disord Drug Targets,2006, 5(2):147-65.
[28] George W. Smith kJ-MA, Francoise Dellu AC, Louise M. Bilezikjian LHG, Ruoping Chen YM, Chris Hauser CAB, Paul E. Sawchenko GFK, Wylie Vale, and Kuo-Fen Lee. Corticotropin Releasing Factor Receptor 1–Deficient Mice Display Decreased Anxiety, Impaired Stress Response, and Aberrant Neuroendocrine Development [J]. Neuron, June, 1998, 20:1093–102.
[29] Nielsen DM. Corticotropin-releasing factor type-1 receptor antagonists: The next class of antidepressants? [J]. Life Sciences, 2006, 78:909– 19.
[30] Nielsen DM. Corticotropin-releasing factor type-1 receptor antagonists: the next class of antidepressants? [J]. Life Sci, 2006, 78(9):909-19.
[31] Gross RS GZ, Dyck B, Coon T, Huang CQ, Lowe RF, Marinkovic D, Moorjani M, Nelson J, Zamani-Kord S, Grigoriadis DE, Hoare SR, Crowe PD, Bu JH, Haddach M, McCarthy J, Saunders J, Sullivan R, Chen T, Williams JP. Design and synthesis of tricyclic corticotropin-releasing factor-1 antagonists [J]. J Med Chem, 2005, 48(18):5780-93.
[32] McCarthy JR, Heinrichs SC, Grigoriadis DE. Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications [J]. Curr Pharm Des, 1999, 5(5):289-315.
[33] Ising M, Holsboer F. CRH1 Receptor Antagonists for the Treatment of Depression and Anxiety [J]. Experimental and Clinical Psychopharmacology 2007:519–28.
[34] Ising M, Zimmermann US, Kunzel HE, Uhr M, Foster AC, Learned-Coughlin SM, et al. High-affinity CRF1 receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response [J]. Neuropsychopharmacology, 2007, 32(9):1941-9.
[35] Heike E. Ku¨nzel AWZ, Thomas Nickel, Nibal Ackl, Manfred Uhr,, Annette Sonntag MI, Florian Holsboer. Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects [J]. Psychiatric Research, 2003, 37: 525–33.
[36] Masayuki UCHIDA MS, and Kimiko SHIMIZU. Effects of Urocortin, Corticotropin-Releasing Factor (CRF) Receptor Agonist, and Astressin, CRF Receptor Antagonist, on the Sleep–Wake Pattern: Analysis by Radiotelemetry in Conscious Rats [J]. Biol Pharm Bull, 2007, 30(10):1895-7.
[37] George Zislis TVD, Melissa Prado, Hina P. Shah, M.D., and Adrie W. Bruijnzeel, Ph.D. Effects of the CRF receptor antagonist D-Phe CRF(12-41) and theα2-adrenergic receptor agonist clonidine on stress-induced reinstatement of nicotine-seeking behavior in rats [J]. Neuropharmacology 2007 December, 53(8):958–66.
[38] McGregor DP. Discovering and improving novel peptide therapeutics [J]. CurrentOpinion in Pharmacology, 2008, 8:616–9.
[39] Noppe W, Plieva F, Galaev IY, Pottel H, Deckmyn H, Mattiasson B. Chromato -panning: an efficient new mode of identifying suitable ligands from phage display libraries [J]. BMC Biotechnol, 2009, 9:21.
[40] Li M. Applications of display technology in protein analysis [J]. Nat Biotechnol, 2000, 18(12):1251-6.
[41] Sam R. J. Hoare SKS, David A. Schwarz, Nicholas Ling, Wylie W. Vale, Paul D. Crowe, and Dimitri E. Grigoriadis. Ligand Affinity for Amino-Terminal and Juxtamembrane Domains of the Corticotropin Releasing Factor Type I Receptor: Regulation by G-Protein and Nonpeptide Antagonists [J]. Biochemistry, 2004, 43 (13): 3996–4011.
[42] CARRIOM M VA. Construction and deconstruction of bacterial inclusion bodies [J]. J Biotechnol, 2002, 96:3- 12.
[43] HOFFMANN F VDHJ, ZIDEK N. Minimizing inclusion body formation during recombinant protein production in Escherichia coli at bench and pilot plant scale [J]. EnzymeMicrobTechnol, 2004, 34:235- 41.
[44] Pande J, Szewczyk MM, Grover AK. Phage display: concept, innovations, applications and future [J]. Biotechnol Adv, 28(6):849-58.
[45] Adda CG, Anders RF, Tilley L, Foley M. Random sequence libraries displayed on phage: identification of biologically important molecules [J]. Comb Chem High Throughput Screen, 2002, 5(1):1-14.
[46] Richard L. Hauger, Victoria Risbrough, Olaf Brauns, and Frank M. Dautzenberg. Corticotropin Releasing Factor (CRF) Receptor Signaling in the Central Nervous System: New Molecular Targets [J]. CNS Neurol Disord Drug Targets, 2006, 5(4):453–79.
[47] Wille S, Sydow S, Palchaudhuri MR, Spiess J, Dautzenberg FM. Identification of amino acids in the N-terminal domain of corticotropin-releasing factor receptor 1 that are important determinants of high-affinity ligand binding [J]. J Neurochem, 1999, 72(1):388-95.
[48] Perrin MH, Fischer WH, Kunitake KS, Craig AG, Koerber SC, Cervini LA, et al. Expression, purification, and characterization of a soluble form of the first extracellular domain of the human type 1 corticotropin releasing factor receptor [J]. J Biol Chem, 2001, 276(34):31528-34.
[49] Perrin MH, DiGruccio MR, Koerber SC, Rivier JE, Kunitake KS, Bain DL, et al. A soluble form of the first extracellular domain of mouse type 2beta corticotropin-releasing factor receptor reveals differential ligand specificity [J]. J Biol Chem, 2003, 278(18):15595-600.
[50] Dautzenberg FM, Kilpatrick GJ, Wille S, Hauger RL. The ligand-selective domainsof corticotropin-releasing factor type 1 and type 2 receptor reside in different extracellular domains: generation of chimeric receptors with a novel ligand -selective profile [J]. J Neurochem, 1999, 73(2):821-9.
[51] Dautzenberg FM, Wille S, Lohmann R, Spiess J. Mapping of the ligand-selective domain of the Xenopus laevis corticotropin-releasing factor receptor 1: implications for the ligand-binding site [J]. Proc Natl Acad Sci U S A, 1998, 95(9):4941-6.
[52] Dautzenberg FM, Wille S. Binding differences of human and amphibian corticotropin-releasing factor type 1 (CRF(1)) receptors: identification of amino acids mediating high-affinity astressin binding and functional antagonism [J]. Regul Pept, 2004, 118(3):165-73.
[53] Hoare SR, Sullivan SK, Fan J, Khongsaly K, Grigoriadis DE. Peptide ligand binding properties of the corticotropin-releasing factor (CRF) type 2 receptor: pharmacology of endogenously expressed receptors, G-protein-coupling sensitivity and determinants of CRF2 receptor selectivity [J]. Peptides, 2005, 26(3):457-70.
[54] Liaw CW, Grigoriadis DE, Lorang MT, De Souza EB, Maki RA. Localization of agonist- and antagonist-binding domains of human corticotropin-releasing factor receptors [J]. Mol Endocrinol, 1997, 11(13):2048-53.
[55] Liaw CW, Grigoriadis DE, Lovenberg TW, De Souza EB, Maki RA. Localization of ligand-binding domains of human corticotropin-releasing factor receptor: a chimeric receptor approach [J]. Mol Endocrinol, 1997, 11(7):980-5.
[56] Perrin MH, Sutton S, Bain DL, Berggren WT, Vale WW. The first extracellular domain of corticotropin releasing factor-R1 contains major binding determinants for urocortin and astressin [J]. Endocrinology, 1998, 139(2):566-70.
[57] Nielsen SM, Nielsen LZ, Hjorth SA, Perrin MH, Vale WW. Constitutive activation of tethered-peptide/corticotropin-releasing factor receptor chimeras [J]. Proc Natl Acad Sci U S A, 2000, 97(18):10277-81.
[58] Hoare SR, Sullivan SK, Ling N, Crowe PD, Grigoriadis DE. Mechanism of corticotropin -releasing factor type I receptor regulation by nonpeptide antagonists [J]. Mol Pharmacol, 2003, 63(3):751-65.
[59] Grigoriadis DE. Expert Opin TherTargets [J]. 2005, 9:651–84.
[60] Hoare SR, Sullivan SK, Pahuja A, Ling N, Crowe PD, Grigoriadis DE. Conformational states of the corticotropin releasing factor 1 (CRF1) receptor: detection, and pharmacological evaluation by peptide ligands [J]. Peptides, 2003, 24(12):1881-97.
[61] Hauger RL, Grigoriadis DE, Dallman MF, Plotsky PM, Vale WW, Dautzenberg FM. International Union of Pharmacology. XXXVI. Current status of the nomenclature for receptors for corticotropin-releasing factor and their ligands [J].Pharmacol Rev, 2003, 55(1):21-6.
[62] Olaf Brauns SB, Bodo Zimmermann, Olaf Jahn, Joachim Spiess. Differential responsiveness of CRF receptor subtypes to N-terminal truncation of peptidic ligands [J]. Peptides 2002, 23:881–8.
[63] H Berger NH, D Wietfeld, M Bienert and M Beyermann. Evidence that corticotropin-releasing factor receptor type 1 couples to Gs- and Gi-proteins through different conformations of its J-domain [J]. British Journal of Pharmacology, 2006, 149:942–7.
[1] WHO Media centre, Mental and neurological disorders, Fact sheet N 265, [J]. 2001.
[2] Jacobi F, Wittchen HU, Holting C, Hofler M, Pfister H, Muller N, et al. Prevalence, co-morbidity and correlates of mental disorders in the general population: results from the German Health Interview and Examination Survey (GHS) [J]. Psychol Med, 2004, 34(4):597-611.
[3] Kessler RC. Epidemiology of women and depression [J]. J Affect Disord, 2003, 74(1):5-13.
[4] Murray C LA. Summary: the global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Harvard School of Public Health on behalf of the World Health Organization and the World Bank. Harvard University Press, Cambridge; [J]. 1996.
[5] Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice [J]. Am J Psychiatry, 2006, 163(1):28-40.
[6] Kroenke K, West SL, Swindle R, Gilsenan A, Eckert GJ, Dolor R, et al. Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: a randomized trial [J]. Jama, 2001, 286(23):2947-55.
[7] Luo L, Rodriguez E, Jerbi K, Lachaux JP, Martinerie J, Corbetta M, et al. Ten years of Nature Reviews Neuroscience: insights from the highly cited [J]. Nat Rev Neurosci, 11(10):718-26.
[8] Uhr M, Tontsch A, Namendorf C, Ripke S, Lucae S, Ising M, et al. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression [J]. Neuron, 2008, 57(2):203-9.
[9] van Rossum EF, Binder EB, Majer M, Koper JW, Ising M, Modell S, et al. Polymorphisms of the glucocorticoid receptor gene and major depression [J]. Biol Psychiatry, 2006, 59(8):681-8.
[10] Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B, et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment [J]. Nat Genet, 2004, 36(12):1319-25.
[11] Francis DD, Caldji C, Champagne F, Plotsky PM, Meaney MJ. The role of corticotropin-releasing factor--norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses tostress [J]. Biol Psychiatry, 1999, 46(9):1153-66.
[12] Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB. The link between childhood trauma and depression: insights from HPA axis studies in humans [J]. Psychoneuroendocrinology, 2008, 33(6):693-710.
[13] Holsboer F. The corticosteroid receptor hypothesis of depression [J]. Neuropsycho -pharmacology, 2000, 23(5):477-501.
[14] Pacher P, Kohegyi E, Kecskemeti V, Furst S. Current trends in the development of new antidepressants [J]. Curr Med Chem, 2001, 8(2):89-100.
[15] Shelton RC. The dual-action hypothesis: does pharmacology matter? [J]. J Clin Psychiatry, 2004, 65 Suppl 17:5-10.
[16] Holsboer F. The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety [J]. J Psychiatr Res, 1999, 33(3):181-214.
[17] Schmidt MV, Trumbach D, Weber P, Wagner K, Scharf SH, Liebl C, et al. Individual stress vulnerability is predicted by short-term memory and AMPA receptor subunit ratio in the hippocampus [J]. J Neurosci, 30(50):16949-58.
[18] Rivier J, Spiess J, Vale W. Characterization of rat hypothalamic corticotrophin -releasing factor [J]. Proc Natl Acad Sci U S A, 1983, 80(15):4851-5.
[19] Smith SM VW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. [J]. Dialogues Clin Neurosci 2006, 8:383-95.
[20] Thomson F, Craighead M. Innovative approaches for the treatment of depression: targeting the HPA axis [J]. Neurochem Res, 2008, 33(4):691-707.
[21] Gray TS. Amygdaloid CRF pathways. Role in autonomic, neuroendocrine, and behavioral responses to stress [J]. Ann N Y Acad Sci, 1993, 697:53-60.
[22] Lehnert H, Schulz C, Dieterich K. Physiological and neurochemical aspects of corticotropin-releasing factor actions in the brain: the role of the locus coeruleus [J]. Neurochem Res, 1998, 23(8):1039-52.
[23] Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB. The role of corticotrophin -releasing factor in depression and anxiety disorders [J]. J Endocrinol, 1999, 160(1):1-12.
[24] Ising M, Kunzel HE, Binder EB, Nickel T, Modell S, Holsboer F. The combined dexamethasone/CRH test as a potential surrogate marker in depression [J]. Prog Neuropsychopharmacol Biol Psychiatry, 2005, 29(6):1085-93.
[25] Pariante CM, Miller AH. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment [J]. Biol Psychiatry, 2001, 49(5):391-404.
[26] Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders [J]. Am J Psychiatry, 2003, 160(9):1554-65.
[27] Holsboer F, Muller OA, Doerr HG, Sippell WG, Stalla GK, Gerken A, et al. ACTH and multisteroid responses to corticotropin-releasing factor in depressive illness: relationship to multisteroid responses after ACTH stimulation and dexamethasone suppression [J]. Psychoneuroendocrinology, 1984, 9(2):147-60.
[28] Gold PW, Chrousos G, Kellner C, Post R, Roy A, Augerinos P, et al. Psychiatric implications of basic and clinical studies with corticotropin-releasing factor [J]. Am J Psychiatry, 1984, 141(5):619-27.
[29] Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K, et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreac -tivity in depressed patients [J]. Science, 1984, 226(4680):1342-4.
[30] Nemeroff CB, Owens MJ, Bissette G, Andorn AC, Stanley M. Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims [J]. Arch Gen Psychiatry, 1988, 45(6):577-9.
[31] Hartline KM, Owens MJ, Nemeroff CB. Postmortem and cerebrospinal fluid studies of corticotropin-releasing factor in humans [J]. Ann N Y Acad Sci, 1996, 780:96-105.
[32] Heuser I, Bissette G, Dettling M, Schweiger U, Gotthardt U, Schmider J, et al. Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: response to amitriptyline treatment [J]. Depress Anxiety, 1998, 8(2):71-9.
[33] Merali Z, Du L, Hrdina P, Palkovits M, Faludi G, Poulter MO, et al. Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region [J]. J Neurosci, 2004, 24(6):1478-85.
[34] Raadsheer FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothala -mic paraventricular nucleus of depressed patients [J]. Neuroendocrin -ology, 1994, 60(4):436-44.
[35] Holsboer F, Ising M. Stress hormone regulation: biological role and translation into therapy [J]. Annu Rev Psychol, 61:81-109, C1-11.
[36] Holsboer F. Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy [J]. J Affect Disord, 2001, 62(1-2):77-91.
[37] Nemeroff CB, Bissette G, Akil H, Fink M. Neuropeptide concentrations in the cerebrospinal fluid of depressed patients treated with electroconvulsive therapy. Corticotrophin-releasing factor, beta-endorphin and somatostatin [J]. Br J Psychiatry, 1991, 158:59-63.
[38] Holsboer F, Liebl R, Hofschuster E. Repeated dexamethasone suppression test during depressive illness. Normalisation of test result compared with clinicalimprovement [J]. J Affect Disord, 1982, 4(2):93-101.
[39] Ising M, Horstmann S, Kloiber S, Lucae S, Binder EB, Kern N, et al. Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression - a potential biomarker? [J]. Biol Psychiatry, 2007, 62(1):47-54.
[40] Reul JM, Stec I, Soder M, Holsboer F. Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary -adrenocortical system [J]. Endocrinology, 1993, 133(1):312-20.
[41] de Kloet ER, Sibug RM, Helmerhorst FM, Schmidt MV. Stress, genes and the mechanism of programming the brain for later life [J]. Neurosci Biobehav Rev, 2005, 29(2):271-81.
[42] Orozco-Cabal L, Pollandt S, Liu J, Shinnick-Gallagher P, Gallagher JP. Regulation of synaptic transmission by CRF receptors [J]. Rev Neurosci, 2006, 17(3):279-307.
[43] Chalmers DT, Lovenberg TW, De Souza EB. Localization of novel corticotrophin -releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression [J]. J Neurosci, 1995, 15(10):6340-50.
[44] McEwen BS. Mood disorders and allostatic load [J]. Biol Psychiatry, 2003, 54(3):200-7.
[45] Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications [J]. Psychopharmacology (Berl), 2004, 174(1):151-62.
[46] Chen Y, Bender RA, Brunson KL, Pomper JK, Grigoriadis DE, Wurst W, et al. Modulation of dendritic differentiation by corticotropin-releasing factor in the developing hippocampus [J]. Proc Natl Acad Sci U S A, 2004, 101(44):15782-7.
[47] Lewis K, Li C, Perrin MH, Blount A, Kunitake K, Donaldson C, et al. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor [J]. Proc Natl Acad Sci U S A, 2001, 98(13):7570-5.
[48] Hsu SY, Hsueh AJ. Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor [J]. Nat Med, 2001, 7(5):605-11.
[49] Reyes TM, Lewis K, Perrin MH, Kunitake KS, Vaughan J, Arias CA, et al. Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors [J]. Proc Natl Acad Sci U S A, 2001, 98(5):2843-8.
[50] Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin [J]. Science, 1981, 213(4514):1394-7.
[51] Perrin MH, Donaldson CJ, Chen R, Lewis KA, Vale WW. Cloning and functional expression of a rat brain corticotropin releasing factor (CRF) receptor [J]. Endocrinology, 1993, 133(6):3058-61.
[52] Chen R, Lewis KA, Perrin MH, Vale WW. Expression cloning of a human corticotropin-releasing-factor receptor [J]. Proc Natl Acad Sci U S A, 1993, 90(19):8967-71.
[53] Vamvakopoulos NC, Sioutopoulou TO. Human corticotropin-releasing hormone receptor gene (CRHR) is located on the long arm of chromosome 17 (17q12-qter) [J]. Chromosome Res, 1994, 2(6):471-3.
[54] Polymeropoulos MH, Torres R, Yanovski JA, Chandrasekharappa SC, Ledbetter DH. The human corticotropin-releasing factor receptor (CRHR) gene maps to chromosome 17q12-q22 [J]. Genomics, 1995, 28(1):123-4.
[55] Chang CP, Pearse RV, 2nd, O'Connell S, Rosenfeld MG. Identification of a seven transmembrane helix receptor for corticotropin-releasing factor and sauvagine in mammalian brain [J]. Neuron, 1993, 11(6):1187-95.
[56] Vita N, Laurent P, Lefort S, Chalon P, Lelias JM, Kaghad M, et al. Primary structure and functional expression of mouse pituitary and human brain corticotrophin releasing factor receptors [J]. FEBS Lett, 1993, 335(1):1-5.
[57] Yu J, Xie LY, Abou-Samra AB. Molecular cloning of a type A chicken corticotropin-releasing factor receptor with high affinity for urotensin I [J]. Endocrinology, 1996, 137(1):192-7.
[58] Dautzenberg FM, Dietrich K, Palchaudhuri MR, Spiess J. Identification of two corticotropin-releasing factor receptors from Xenopus laevis with high ligand selectivity: unusual pharmacology of the type 1 receptor [J]. J Neurochem, 1997, 69(4):1640-9.
[59] Myers DA, Trinh JV, Myers TR. Structure and function of the ovine type 1 corticotropin releasing factor receptor (CRF1) and a carboxyl-terminal variant [J]. Mol Cell Endocrinol, 1998, 144(1-2):21-35.
[60] Ross PC, Kostas CM, Ramabhadran TV. A variant of the human corticotrophin -releasing factor (CRF) receptor: cloning, expression and pharmacology [J]. Biochem Biophys Res Commun, 1994, 205(3):1836-42.
[61] Grammatopoulos DK, Dai Y, Randeva HS, Levine MA, Karteris E, Easton AJ, et al. A novel spliced variant of the type 1 corticotropin-releasing hormone receptor with a deletion in the seventh transmembrane domain present in the human pregnant term myometrium and fetal membranes [J]. Mol Endocrinol, 1999, 13(12): 2189-202.
[62] Hoare SR, Sullivan SK, Pahuja A, Ling N, Crowe PD, Grigoriadis DE. Conformational states of the corticotropin releasing factor 1 (CRF1) receptor:detection, and pharmacological evaluation by peptide ligands [J]. Peptides, 2003, 24(12):1881-97.
[63] Hoare SR. Mechanisms of peptide and nonpeptide ligand binding to Class B G-protein-coupled receptors [J]. Drug Discov Today, 2005, 10(6):417-27.
[64] Grigoriadis DE, Hoare SR, Lechner SM, Slee DH, Williams JA. Drugability of extracellular targets: discovery of small molecule drugs targeting allosteric, functional, and subunit-selective sites on GPCRs and ion channels [J]. Neuropsychopharmacology, 2009, 34(1):106-25.
[65] Lederis K, Letter A, McMaster D, Moore G, Schlesinger D. Complete amino acid sequence of urotensin I, a hypotensive and corticotropin-releasing neuropeptide from Catostomus [J]. Science, 1982, 218(4568):162-5.
[66] Montecucchi PC, Anastasi A, de Castiglione R, Erspamer V. Isolation and amino acid composition of sauvagine. An active polypeptide from methanol extracts of the skin of the South American frog Phyllomedusa sauvagei [J]. Int J Pept Protein Res, 1980, 16(3):191-9.
[67] De Souza EB, Perrin MH, Rivier J, Vale WW, Kuhar MJ. Corticotropin-releasing factor receptors in rat pituitary gland: autoradiographic localization [J]. Brain Res, 1984, 296(1):202-7.
[68] Potter E, Sutton S, Donaldson C, Chen R, Perrin M, Lewis K, et al. Distribution of corticotropin-releasing factor receptor mRNA expression in the rat brain and pituitary [J]. Proc Natl Acad Sci U S A, 1994, 91(19):8777-81.
[69] De Souza EB, Insel TR, Perrin MH, Rivier J, Vale WW, Kuhar MJ. Corticotrophin -releasing factor receptors are widely distributed within the rat central nervous system: an autoradiographic study [J]. J Neurosci, 1985, 5(12):3189-203.
[70] Reul JM, Holsboer F. Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression [J]. Curr Opin Pharmacol, 2002, 2(1):23-33.
[71] Gehlert DR, Shekhar A, Morin SM, Hipskind PA, Zink C, Gackenheimer SL, et al. Stress and central Urocortin increase anxiety-like behavior in the social interaction test via the CRF1 receptor [J]. Eur J Pharmacol, 2005, 509(2-3): 145-53.
[72] Coste SC, Murray SE, Stenzel-Poore MP. Animal models of CRH excess and CRH receptor deficiency display altered adaptations to stress [J]. Peptides, 2001, 22(5):733-41.
[73] Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM, Gold LH, et al. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development [J]. Neuron, 1998, 20(6):1093-102.
[74] Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK, et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotrophin-releasing hormone receptor 1 [J]. Nat Genet, 1998, 19(2):162-6.
[75] Muller MB, Zimmermann S, Sillaber I, Hagemeyer TP, Deussing JM, Timpl P, et al. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress [J]. Nat Neurosci, 2003, 6(10):1100-7.
[76] Coric V, Feldman HH, Oren DA, Shekhar A, Pultz J, Dockens RC, et al. Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder [J]. Depress Anxiety, 27(5):417-25.
[77] Sweetser S, Camilleri M, Linker Nord SJ, Burton DD, Castenada L, Croop R, et al. Do corticotropin releasing factor-1 receptors influence colonic transit and bowel function in women with irritable bowel syndrome? [J]. Am J Physiol Gastrointest Liver Physiol, 2009, 296(6):G1299-306.
[78] Tojo K, Abou-Samra AB. Corticotropin-releasing factor (CRF) stimulates 45Ca2+ uptake in the mouse corticotroph cell line AtT-20 [J]. Life Sci, 1993, 52(7):621-30.
[79] Kovalovsky D, Refojo D, Liberman AC, Hochbaum D, Pereda MP, Coso OA, et al. Activation and induction of NUR77/NURR1 in corticotrophs by CRH/cAMP: involvement of calcium, protein kinase A, and MAPK pathways [J]. Mol Endocrinol, 2002, 16(7):1638-51.
[80] Hoare SR, Sullivan SK, Schwarz DA, Ling N, Vale WW, Crowe PD, et al. Ligand affinity for amino-terminal and juxtamembrane domains of the corticotropin releasing factor type I receptor: regulation by G-protein and nonpeptide antagonists [J]. Biochemistry, 2004, 43(13):3996-4011.
[81] Hoare SR, Brown BT, Santos MA, Malany S, Betz SF, Grigoriadis DE. Single amino acid residue determinants of non-peptide antagonist binding to the corticotropin-releasing factor1 (CRF1) receptor [J]. Biochem Pharmacol, 2006, 72(2):244-55.
[82] Liaw CW, Grigoriadis DE, Lovenberg TW, De Souza EB, Maki RA. Localization of ligand-binding domains of human corticotropin-releasing factor receptor: a chimeric receptor approach [J]. Mol Endocrinol, 1997, 11(7):980-5.
[83] Hoare SR, Fleck BA, Gross RS, Crowe PD, Williams JP, Grigoriadis DE. Allosteric ligands for the corticotropin releasing factor type 1 receptor modulate conformational states involved in receptor activation [J]. Mol Pharmacol, 2008, 73(5):1371-80.
[84] McCarthy JR, Heinrichs SC, Grigoriadis DE. Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications [J]. Curr Pharm Des, 1999, 5(5):289-315.
[85] Gross RS, Guo Z, Dyck B, Coon T, Huang CQ, Lowe RF, et al. Design and synthesis of tricyclic corticotropin-releasing factor-1 antagonists [J]. J Med Chem,2005, 48(18):5780-93.
[86] Saunders J, Williams J. Antagonists of the corticotropin releasing factor receptor [J]. Prog Med Chem, 2003, 41:195-247.
[87] Steckler T, Dautzenberg FM. Corticotropin-releasing factor receptor antagonists in affective disorders and drug dependence-- an update [J]. CNS Neurol Disord Drug Targets, 2006, 5(2):147-65.
[88] Valdez GR. Development of CRF1 receptor antagonists as antidepressants and anxiolytics: progress to date [J]. CNS Drugs, 2006, 20(11):887-96.
[89] Zorrilla EP, Koob GF. The therapeutic potential of CRF1 antagonists for anxiety [J]. Expert Opin Investig Drugs, 2004, 13(7):799-828.
[90] Kehne JH, Cain CK. Therapeutic utility of non-peptidic CRF1 receptor antagonists in anxiety, depression, and stress-related disorders: evidence from animal models [J]. Pharmacol Ther, 128(3):460-87.
[91] Grigoriadis DE. The corticotropin-releasing factor receptor: a novel target for the treatment of depression and anxiety-related disorders [J]. Expert Opin Ther Targets, 2005, 9(4):651-84.
[92] Tellew JE, Luo Z. Small molecule antagonists of the corticotropin releasing factor (CRF) receptor: recent medicinal chemistry developments [J]. Curr Top Med Chem, 2008, 8(6):506-20.
[93] Hemley CF, McCluskey A, Keller PA. Corticotropin releasing hormone--a GPCR drug target [J]. Curr Drug Targets, 2007, 8(1):105-15.
[94] Zorrilla EP, Koob GF. Progress in corticotropin-releasing factor-1 antagonist development [J]. Drug Discov Today, 15(9-10):371-83.
[95] Chen C, Wilcoxen KM, Huang CQ, Xie YF, McCarthy JR, Webb TR, et al. Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1, 5-a]py rimidine (NBI 30775/R121919) and structure--activity relationships of a series of potent and orally active corticotropin-releasing factor receptor antagonists [J]. J Med Chem, 2004, 47(19):4787-98.
[96] Heinrichs SC, De Souza EB, Schulteis G, Lapsansky JL, Grigoriadis DE. Brain penetrance, receptor occupancy and antistress in vivo efficacy of a small molecule corticotropin releasing factor type I receptor selective antagonist [J]. Neuropsycho -pharmacology, 2002, 27(2):194-202.
[97] Held K, Kunzel H, Ising M, Schmid DA, Zobel A, Murck H, et al. Treatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression [J]. J Psychiatr Res, 2004, 38(2):129-36.
[98] Kunzel HE, Zobel AW, Nickel T, Ackl N, Uhr M, Sonntag A, et al. Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects [J]. J Psychiatr Res, 2003, 37(6):525-33.
[99] Kunzel HE, Ising M, Zobel AW, Nickel T, Ackl N, Sonntag A, et al. Treatment with a CRH-1-receptor antagonist (R121919) does not affect weight or plasma leptin concentration in patients with major depression [J]. J Psychiatr Res, 2005, 39(2):173-7.
[100] Zobel AW, Nickel T, Kunzel HE, Ackl N, Sonntag A, Ising M, et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated [J]. J Psychiatr Res, 2000, 34(3):171-81.
[101] Hamilton M. Rating depressive patients [J]. J Clin Psychiatry, 1980, 41(12 Pt 2):21-4.
[102] Kimura M, Muller-Preuss P, Lu A, Wiesner E, Flachskamm C, Wurst W, et al. Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep [J]. Mol Psychiatry, 15(2):154-65.
[103] Holsboer F, von Bardeleben U, Steiger A. Effects of intravenous corticotrophin -releasing hormone upon sleep-related growth hormone surge and sleep EEG in man [J]. Neuroendocrinology, 1988, 48(1):32-8.
[104] Chen YL, Braselton J, Forman J, Gallaschun RJ, Mansbach R, Schmidt AW, et al. Synthesis and SAR of 2-aryloxy-4-alkoxy-pyridines as potent orally active corticotropin-releasing factor 1 receptor antagonists [J]. J Med Chem, 2008, 51(5):1377-84.
[105] Binneman B, Feltner D, Kolluri S, Shi Y, Qiu R, Stiger T. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression [J]. Am J Psychiatry, 2008, 165(5):617-20.
[106] Gilligan PJ, He L, Clarke T, Tivitmahaisoon P, Lelas S, Li YW, et al. 8-(4- Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: selective and centrally active corticotropin-releasing factor receptor-1 (CRF1) antagonists [J]. J Med Chem, 2009, 52(9):3073-83.
[107] Di Fabio R, St-Denis Y, Sabbatini FM, Andreotti D, Arban R, Bernasconi G, et al. Synthesis and pharmacological characterization of novel druglike corticotrophin -releasing factor 1 antagonists [J]. J Med Chem, 2008, 51(23):7370-9.
[108] Tellew JE, Lanier M, Moorjani M, Lin E, Luo Z, Slee DH, et al. Discovery of NBI-77860/GSK561679, a potent corticotropin-releasing factor (CRF1) receptor antagonist with improved pharmacokinetic properties [J]. Bioorg Med Chem Lett, 20(24):7259-64.
[109] Lu A, Steiner MA, Whittle N, Vogl AM, Walser SM, Ableitner M, et al. Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior [J]. Mol Psychiatry, 2008, 13(11): 1028-42.
[110] Licinio J, O'Kirwan F, Irizarry K, Merriman B, Thakur S, Jepson R, et al. Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans [J]. Mol Psychiatry, 2004, 9(12):1075-82.
[111] Lekman M, Laje G, Charney D, Rush AJ, Wilson AF, Sorant AJ, et al. The FKBP5-gene in depression and treatment response--an association study in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Cohort [J]. Biol Psychiatry, 2008, 63(12):1103-10.
[112] Kirchheiner J, Lorch R, Lebedeva E, Seeringer A, Roots I, Sasse J, et al. Genetic variants in FKBP5 affecting response to antidepressant drug treatment [J]. Pharmacogenomics, 2008, 9(7):841-6.
[113] Horstmann S, Lucae S, Menke A, Hennings JM, Ising M, Roeske D, et al. Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment [J]. Neuropsychopharmacology, 35(3):727-40.
[114] Scammell JG, Denny WB, Valentine DL, Smith DF. Overexpression of the FK506-binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three New World primates [J]. Gen Comp Endocrinol, 2001, 124(2):152-65.
[115] Vermeer H, Hendriks-Stegeman BI, van der Burg B, van Buul-Offers SC, Jansen M. Glucocorticoid-induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression: a potential marker for glucocorticoid sensitivity, potency, and bioavailability [J]. J Clin Endocrinol Metab, 2003, 88(1):277-84.
[116] Mennigen JA, Harris EA, Chang JP, Moon TW, Trudeau VL. Fluoxetine affects weight gain and expression of feeding peptides in the female goldfish brain [J]. Regul Pept, 2009, 155(1-3):99-104.
[117] Liu Z, Zhu F, Wang G, Xiao Z, Tang J, Liu W, et al. Association study of corticotropin-releasing hormone receptor1 gene polymorphisms and antidepressa -nt response in major depressive disorders [J]. Neurosci Lett, 2007, 414(2):155-8.
[118] Keck ME, Welt T, Wigger A, Renner U, Engelmann M, Holsboer F, et al. The anxiolytic effect of the CRH(1) receptor antagonist R121919 depends on innate emotionality in rats [J]. Eur J Neurosci, 2001, 13(2):373-80.
[119] Li YW, Hill G, Wong H, Kelly N, Ward K, Pierdomenico M, et al. Receptor occupancy of nonpeptide corticotropin-releasing factor 1 antagonist DMP696: correlation with drug exposure and anxiolytic efficacy [J]. J Pharmacol Exp Ther, 2003, 305(1):86-96.
[120] Gutman DA, Owens MJ, Skelton KH, Thrivikraman KV, Nemeroff CB. The corticotropin-releasing factor1 receptor antagonist R121919 attenuates thebehavioral and endocrine responses to stress [J]. J Pharmacol Exp Ther, 2003, 304(2):874-80.
[121] Gutman DA, Owens MJ, Thrivikraman KV, Nemeroff CB. Persistent anxiolytic affects after chronic administration of the CRF(1) receptor antagonist R121919 in rats [J]. Neuropharmacology, 60(7-8):1135-41.
[122] Chaki S, Nakazato A, Kennis L, Nakamura M, Mackie C, Sugiura M, et al. Anxiolytic- and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450 [J]. Eur J Pharmacol, 2004, 485(1-3):145-58.
[123] Lelas S, Wong H, Li YW, Heman KL, Ward KA, Zeller KL, et al. Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyr imidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats [J]. J Pharmacol Exp Ther, 2004, 309(1):293-302.
[124] Gehlert DR, Cippitelli A, Thorsell A, Le AD, Hipskind PA, Hamdouchi C, et al. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo [1,2-b]pyridazine: a novel brain-penetrant, orally available corticotrophin -releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism [J]. J Neurosci, 2007, 27(10):2718-26.
[125] Ising M, Zimmermann US, Kunzel HE, Uhr M, Foster AC, Learned-Coughlin SM, et al. High-affinity CRF1 receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response [J]. Neuropsychopharmacology, 2007, 32(9):1941-9.
[126] Schmidt ME, Andrews RD, van der Ark P, Brown T, Mannaert E, Steckler T, et al. Dose-dependent effects of the CRF (1) receptor antagonist R317573 on regional brain activity in healthy male subjects [J]. Psychopharmacology (Berl), 208(1):109-19.
[127] Hsin LW, Webster EL, Chrousos GP, Gold PW, Eckelman WC, Contoreggi C, et al. Synthesis and biological activity of fluoro-substituted pyrrolo[2,3-d] pyrimidines: the development of potential positron emission tomography imaging agents for the corticotropin-releasing hormone type 1 receptor [J]. Bioorg Med Chem Lett, 2000, 10(8):707-10.
[128] Hsin LW, Tian X, Webster EL, Coop A, Caldwell TM, Jacobson AE, et al. CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists [J]. Bioorg Med Chem, 2002, 10(1):175-83.
[129] Martarello L, Kilts CD, Ely T, Owens MJ, Nemeroff CB, Camp M, et al. Synthesis and characterization of fluorinated and iodinated pyrrolopyrimidines as PET/SPECT ligands for the CRF1 receptor [J]. Nucl Med Biol, 2001,28(2):187-95.
[130] Kumar JS, Majo VJ, Sullivan GM, Prabhakaran J, Simpson NR, Van Heertum RL, et al. Synthesis and in vivo evaluation of [11C]SN003 as a PET ligand for CRF1 receptors [J]. Bioorg Med Chem, 2006, 14(12):4029-34.
[131] Sullivan GM, Parsey RV, Kumar JS, Arango V, Kassir SA, Huang YY, et al. PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density? [J]. Nucl Med Biol, 2007, 34(4):353-61.