新的苯茚胺类似物的设计合成及抗抑郁活性研究
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摘要
目的:进一步提高一种选择性5-HT重摄取抑制剂(SSRIs)的选择性和抗抑郁活性。方法:通过比较分子力场分析方法(CoMFA),建立有较高的预测能力的苯茚胺类似物抗抑郁活性的三维定量构效模型,研究其结构与活性间的关系,指导设计并优化合成出新的化合物,然后用小鼠悬尾实验进行初步的抗抑郁药理活性的筛选,得到具有抗抑郁活性的新的苯茚胺类似物。结果:该三维定量构效模型的交叉验证相关系数R2CV=0.660,非交叉验证相关系数R2=0.976,标准偏差SEE=0.196,F=181.916;合成新化合物的总收率分别为38%,44%,40%,并经过红外光谱、质谱、核磁共振氢谱对其结构进行了表征;小鼠悬尾实验结果显示化合物4b明显减少了悬尾小鼠的静止时间[(70±30)s,(73±48)s,(66±31)s],与实验对照组相比具有显著统计学意义(P<0.05)。结论:运用该模型指导设计、合成出了新的化合物,活性化合物4b可能是潜在的一种新的SSRIs,值得进一步研究。
AIM To enhance the selectivity and potent anti-depression activity of one kind of selective serotonin reuptake inhibitors (SSRIs). METHODS To quantitively disclose the relationship between structure and actitivety of a series of selective serotonin reuptake inhibitors(SSRIs) for 3-Phenyl -1-indan-amines,and build a three dimensional Quantitative structure activity relationship(3D-QSAR) model for the design of novel potent drugs by the comparative molecular field analysis(CoMFA). then to design and synthesis a series of novel compounds by one of high efficiency routes. The last to obtain new active analogues from them by mouse tail suspension tests. RESULT About 3D-QSAR model ,the cross validation R2CV= 0.660 , non-crossvalidation R2=0.976,standard error of estimate SEE=0.196, F=181.916. The structure of the target compounds were verified by IR,1H-NHR and MS spectra ,and obtained respectively with overall yields of 38%,44% and 40%.The mice that were administered with the compound 4b(40mg/kg) had obviously shorter immobility time than the blank control mice (P<0.05) in mouse tail suspension tests. CONCLUSION The model possesses a high predicta- -bility and offers an approach to design the potent SSRIs, and the compound 4b is worthy to be further investigated in antidepressant activity as SSRIs.
AIM To enhance the selectivity and potent anti-depression activity of one kind of selective serotonin reuptake inhibitors (SSRIs). METHODS To quantitively disclose the relationship between structure and actitivety of a series of selective serotonin reuptake inhibitors(SSRIs) for 3-Phenyl -1-indan-amines,and build a three dimensional Quantitative structure activity relationship(3D-QSAR) model for the design of novel potent drugs by the comparative molecular field analysis(CoMFA). then to design and synthesis a series of novel compounds by one of high efficiency routes. The last to obtain new active analogues from them by mouse tail suspension tests. RESULT About 3D-QSAR model ,the cross validation R2CV= 0.660 , non-crossvalidation R2=0.976,standard error of estimate SEE=0.196, F=181.916. The structure of the target compounds were verified by IR,1H-NHR and MS spectra ,and obtained respectively with overall yields of 38%,44% and 40%.The mice that were administered with the compound 4b(40mg/kg) had obviously shorter immobility time than the blank control mice (P<0.05) in mouse tail suspension tests. CONCLUSION The model possesses a high predicta- -bility and offers an approach to design the potent SSRIs, and the compound 4b is worthy to be further investigated in antidepressant activity as SSRIs.
引文
[1]Stephen M. Stahl,Essential Psychopharmacology:Neuroscientific Basis and Practical Applica- -tions [M]. Cambridge : Cambridge University Press ,second edition,2000,199-231
[2]Vaswani M, Linda FK, Ramesh S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2003, 27(1): 85-89
[3] Nutt DJ, Forshall S, Argyropoulos S,et al.Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders [J]. Eur Neuropsychopharmacol 1999 ; 9 (Suppl 3):S81-
[4] Cramer R D,Patterson D E. Effect of shape onbinding of steroids to carrier proteins[J]. J Am Chem Soc,1998,110(18):5959-5967.
[5]B￠ges￠ K P. Neurooleptic Activity and Dopamine-Uptake Inhibition in 1-Piperazino-3 -Phenylindans[J]. J Med Chem,1983,26(7):935-947.
[6]B￠ges￠ K P, Hyttel J, Christensen A V, et al. 3-Phenyl-1-indanamines.Potential Antidepressant Activity and Potent Inhibition of Dopamine,Norepinephrine,and Serotonin Uptake[J]. J Med Chem,1985,28(12):1817-1823
[7]Dean PM and Lewis RA. Molecular diversity in drug design.[M].Kluwer Academic Publi- -shers,1999
[8]Kubinyi H.Similarity and dissimilarity:a medicinal chemist’s view.Perspet Drug Disc Des, 1998 ,9/10/11,225-252
[9]郭宗儒,药物分子设计,[M].科学出版社,第一版,2005
[10] Klaus P. B￠ges￠, Anders S.Toft. 1-dimethylaminopropyl-1-phenyl phthalans [p]. US4136139
[11]R.M.普拉,C.N.文凯西. 西酞普兰的制备方法.[P]02805419.9
[12]Petersen.Hans.Method for the preparation of citalopram.[P].WO99/30548
[13]J.达尔阿斯塔,U.卡萨扎,H.彼德森. 西酞普兰的制备方法.[P]99812369.2
[14] H.彼德森,J.菲尔丁. 制备西酞普兰的方法.[P]99817098.4
[15] H.彼德森,H.阿马蒂安,R.丹瑟. 制备西酞普兰的方法.[P]01133948.9
[16] Petersen.Hans,Guldagervej.Ll. Method for the preparation of citalopram .[P]. WO98/19512
[17] Bogeso; Klaus P. Novel intermediate and method for its preparation [P].US.4650884
[18] Petersen.Hans,Klaus .Peter,Michael Bech. Method for the preparation of citalopram [P] WO 98/19511
[19] Rock Milcheal, Petersen Hans, Ellegaard Peter . A method for the preparation of citalopram [P]WO00/12044
[20]余红霞,郭峰. 西酞普兰合成路线图解. [J].中国医药工业杂志,2003,34(10)535-536
[21]王葆仁,有机合成反应(下),[M].科学出版社,第一版,1981
[22]吴秋业,廖红利,赵惠清等. 氢溴酸西酞普兰的合成.[J].中国医药工业杂志2005,36(1)6-7
[23]姚新生主编. 有机化合物波谱分析[M]. 中国医药科技出版社.第一版 2004
[24]唐恢同编著.有机化合物的光谱鉴定.[M].北京大学出版社.第一版 1992.
[25]张均田,药理学实验方法.[M].北京医科大学中国协和医科大学联合出版社. 1998
[1] Vaswani M, Linda FK, Ramesh S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review[J]. Prog Neuropsychopharmacol Biol Psychiatry,2003,27(1):85
[2] Montgomery SA, Loft H, Sanchez C, Reines EH, Papp M. Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model [J]. Pharmacol Toxicol,2001,88(5):282
[3] Hyttel J.Arnt J,Sanchez C.The pharmacology of citalopram [J].Rev Contemp Pharmacother,1995,6:271
[4] Stone KJ, Viera AJ, Parman CL. Off-label applications for SSRIs [J]. Am Fam Physician. 2003,68(3):498
[5] Priskorn M ,Larseen F,et a1.Pharmacokinetic interaction study of citalopram and cimetidine in healthy subjects[J].Eur J Clin Pharmacol, 1997,52:241
[6] Baumann P,Larsen F . The pharmacokinetics of citalopram[J].Rev Contemp Pharmacother,1995,6(6):287
[7] Nakamura M ,Ueno S,Sano A ,et a1.The human serotonin transporter gene linked ploymorphism,(5-HTTLPR) shows ten novel allelic variants[J].Mol Psychiatry, 2000,5(1):32
[8] Smeraldi E,Zanardi R,Benedetti F,et a1.Polymorphism within the promoter 0f the serotonin transporter gene and antidepressant efficacy of fluvoxa -mine[J].Mol Psychiatry,1998,3 (6):508
[9] Yu YW ,Tsai SJ,Chen TJ ,et a1.Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepres -sant response in major depressive disorders[J].Mol Psychiatry,2002,7(1O):1115
[10] Rausch JL,John ME,Fei YJ,et a1.Initial conditions of seroionin transporter kinetics and genbtype : influence on SSRI treatment trial outcome[J].Biol Psychiatry,2002 ,51 (9):723
[11]Whale R,Quested DJ,Lavez D,et a1.Serotonin transporter (5-HTT)Promoter genotype may influence the prolactin response to clomipramine[J]. Psychopharmacology (Berl),2000,150 (1):120
[12] Kim DK,Lim SW ,Sohn SE,et a1.Serotonin transporter gene polymorphism and antidepressant i-esponse[J].Neuroreport,2000,11 (1):215
[13] Martinez J , Perez S , et a1 . New 3-[4-(ary1) piperazin-1-y1] -l-(benzo[b]thiophen-3-y1) propane derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a newclass of antidepre -ssants[J].European Journal of Medicinal Chemistry,2001,36(1):55
[14]Dorsey JM, Miranda MG, Cozzi NV, Pinney KG. Synthesis and biological evaluation of 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines as serotonin selective reuptake inhibitors with a potentially improved adverse reaction profile[J]. Bioorg Med Chem. 2004,12(6):1483
[15]Davies HML,Kuhn LA,Thomley C,et a1.Synthesis of 3β-aryl-8-azabicyclo [3.2.1]octanes with binding affinities and selectivities for the serotonintransportersite[J].Journal of Medicinal Chemistry.1996,39 (13):2554
[16] Arthur J,Mayorga A D.Antidepressant-like behaxioral effection 5-hydroxy trypatamine 1A an d 5 一 hydroxytryptamine lB receptor mutant mice[J].J Pharmacol Exp Ther,2001,298(9):l101
[17] 陈芳萍,李运曼,刘国卿.5-HT1A 受体激动剂抗抑郁药的研究与开发[J].药学进展,2003,27(4):213
[2]Vaswani M, Linda FK, Ramesh S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2003, 27(1): 85-89
[3] Nutt DJ, Forshall S, Argyropoulos S,et al.Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders [J]. Eur Neuropsychopharmacol 1999 ; 9 (Suppl 3):S81-
[4] Cramer R D,Patterson D E. Effect of shape onbinding of steroids to carrier proteins[J]. J Am Chem Soc,1998,110(18):5959-5967.
[5]B￠ges￠ K P. Neurooleptic Activity and Dopamine-Uptake Inhibition in 1-Piperazino-3 -Phenylindans[J]. J Med Chem,1983,26(7):935-947.
[6]B￠ges￠ K P, Hyttel J, Christensen A V, et al. 3-Phenyl-1-indanamines.Potential Antidepressant Activity and Potent Inhibition of Dopamine,Norepinephrine,and Serotonin Uptake[J]. J Med Chem,1985,28(12):1817-1823
[7]Dean PM and Lewis RA. Molecular diversity in drug design.[M].Kluwer Academic Publi- -shers,1999
[8]Kubinyi H.Similarity and dissimilarity:a medicinal chemist’s view.Perspet Drug Disc Des, 1998 ,9/10/11,225-252
[9]郭宗儒,药物分子设计,[M].科学出版社,第一版,2005
[10] Klaus P. B￠ges￠, Anders S.Toft. 1-dimethylaminopropyl-1-phenyl phthalans [p]. US4136139
[11]R.M.普拉,C.N.文凯西. 西酞普兰的制备方法.[P]02805419.9
[12]Petersen.Hans.Method for the preparation of citalopram.[P].WO99/30548
[13]J.达尔阿斯塔,U.卡萨扎,H.彼德森. 西酞普兰的制备方法.[P]99812369.2
[14] H.彼德森,J.菲尔丁. 制备西酞普兰的方法.[P]99817098.4
[15] H.彼德森,H.阿马蒂安,R.丹瑟. 制备西酞普兰的方法.[P]01133948.9
[16] Petersen.Hans,Guldagervej.Ll. Method for the preparation of citalopram .[P]. WO98/19512
[17] Bogeso; Klaus P. Novel intermediate and method for its preparation [P].US.4650884
[18] Petersen.Hans,Klaus .Peter,Michael Bech. Method for the preparation of citalopram [P] WO 98/19511
[19] Rock Milcheal, Petersen Hans, Ellegaard Peter . A method for the preparation of citalopram [P]WO00/12044
[20]余红霞,郭峰. 西酞普兰合成路线图解. [J].中国医药工业杂志,2003,34(10)535-536
[21]王葆仁,有机合成反应(下),[M].科学出版社,第一版,1981
[22]吴秋业,廖红利,赵惠清等. 氢溴酸西酞普兰的合成.[J].中国医药工业杂志2005,36(1)6-7
[23]姚新生主编. 有机化合物波谱分析[M]. 中国医药科技出版社.第一版 2004
[24]唐恢同编著.有机化合物的光谱鉴定.[M].北京大学出版社.第一版 1992.
[25]张均田,药理学实验方法.[M].北京医科大学中国协和医科大学联合出版社. 1998
[1] Vaswani M, Linda FK, Ramesh S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review[J]. Prog Neuropsychopharmacol Biol Psychiatry,2003,27(1):85
[2] Montgomery SA, Loft H, Sanchez C, Reines EH, Papp M. Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model [J]. Pharmacol Toxicol,2001,88(5):282
[3] Hyttel J.Arnt J,Sanchez C.The pharmacology of citalopram [J].Rev Contemp Pharmacother,1995,6:271
[4] Stone KJ, Viera AJ, Parman CL. Off-label applications for SSRIs [J]. Am Fam Physician. 2003,68(3):498
[5] Priskorn M ,Larseen F,et a1.Pharmacokinetic interaction study of citalopram and cimetidine in healthy subjects[J].Eur J Clin Pharmacol, 1997,52:241
[6] Baumann P,Larsen F . The pharmacokinetics of citalopram[J].Rev Contemp Pharmacother,1995,6(6):287
[7] Nakamura M ,Ueno S,Sano A ,et a1.The human serotonin transporter gene linked ploymorphism,(5-HTTLPR) shows ten novel allelic variants[J].Mol Psychiatry, 2000,5(1):32
[8] Smeraldi E,Zanardi R,Benedetti F,et a1.Polymorphism within the promoter 0f the serotonin transporter gene and antidepressant efficacy of fluvoxa -mine[J].Mol Psychiatry,1998,3 (6):508
[9] Yu YW ,Tsai SJ,Chen TJ ,et a1.Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepres -sant response in major depressive disorders[J].Mol Psychiatry,2002,7(1O):1115
[10] Rausch JL,John ME,Fei YJ,et a1.Initial conditions of seroionin transporter kinetics and genbtype : influence on SSRI treatment trial outcome[J].Biol Psychiatry,2002 ,51 (9):723
[11]Whale R,Quested DJ,Lavez D,et a1.Serotonin transporter (5-HTT)Promoter genotype may influence the prolactin response to clomipramine[J]. Psychopharmacology (Berl),2000,150 (1):120
[12] Kim DK,Lim SW ,Sohn SE,et a1.Serotonin transporter gene polymorphism and antidepressant i-esponse[J].Neuroreport,2000,11 (1):215
[13] Martinez J , Perez S , et a1 . New 3-[4-(ary1) piperazin-1-y1] -l-(benzo[b]thiophen-3-y1) propane derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a newclass of antidepre -ssants[J].European Journal of Medicinal Chemistry,2001,36(1):55
[14]Dorsey JM, Miranda MG, Cozzi NV, Pinney KG. Synthesis and biological evaluation of 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines as serotonin selective reuptake inhibitors with a potentially improved adverse reaction profile[J]. Bioorg Med Chem. 2004,12(6):1483
[15]Davies HML,Kuhn LA,Thomley C,et a1.Synthesis of 3β-aryl-8-azabicyclo [3.2.1]octanes with binding affinities and selectivities for the serotonintransportersite[J].Journal of Medicinal Chemistry.1996,39 (13):2554
[16] Arthur J,Mayorga A D.Antidepressant-like behaxioral effection 5-hydroxy trypatamine 1A an d 5 一 hydroxytryptamine lB receptor mutant mice[J].J Pharmacol Exp Ther,2001,298(9):l101
[17] 陈芳萍,李运曼,刘国卿.5-HT1A 受体激动剂抗抑郁药的研究与开发[J].药学进展,2003,27(4):213