水杨酰苯胺类mglu5拮抗剂的设计、合成及活性研究
|
摘要
目的利用骨架跃迁思想设计并合成新型水杨酰苯胺类代谢型谷氨酸受体5(metabotropic glutamate receptor5,mglu5)拮抗剂。方法将取代水杨酸与二取代苯胺缩合得目标化合物Ⅰ-Ⅳ,用核磁共振和质谱进行结构确证,荧光测钙流法进行拮抗mglu5活性测定。结果设计的目标化合物对mglu5具有明显的拮抗活性,其中化合物Ⅰ拮抗活性最好,IC_(50)为0.079μmol/L。结论水杨酰苯胺类化合物为潜在的新型mglu5拮抗剂,值得进一步研究。
Objective To design, synthesis and activity screening of salicylanilides as new mglu5 receptor antagonist.Methods A scaffold hopping approach has been exploited to design a novel class of mglu5 receptor antagonists Ⅰ-Ⅳ.The design compounds were synthesized by using salicylic acids and anilines. The structures of target compounds were identified by NMR and MS. The activity of mglu 5 was screened by Ca~(2+) mobilization assay. Results The designed salicylanilides show potent antagonistic activity to mglu5 receptor in vitro. Among them, compound Ⅰ was the best, and IC_(50) of compound Ⅰ was0.079 μmol/L. Conclusion The salicylanilides were new potent mglu5 receptor antagonist and worth to be further studied.
Objective To design, synthesis and activity screening of salicylanilides as new mglu5 receptor antagonist.Methods A scaffold hopping approach has been exploited to design a novel class of mglu5 receptor antagonists Ⅰ-Ⅳ.The design compounds were synthesized by using salicylic acids and anilines. The structures of target compounds were identified by NMR and MS. The activity of mglu 5 was screened by Ca~(2+) mobilization assay. Results The designed salicylanilides show potent antagonistic activity to mglu5 receptor in vitro. Among them, compound Ⅰ was the best, and IC_(50) of compound Ⅰ was0.079 μmol/L. Conclusion The salicylanilides were new potent mglu5 receptor antagonist and worth to be further studied.
引文
[1]Wijetunge LS,Till SM,Gillingwater TH,et al.m Glu R5 regulates glutamate-dependent development of the mouse somatosensory cortex[J].J Neurosci,2008,28(49):13028-13037.
[2]Wu YL,Wang NN,Gu L,et al.The suppressive effect of metabotropic glutamate receptor 5(m Glu5)inhibition on hepa tocarcinogenesis[J].Biochimie,2012,94(11):2366-2375.
[3]Varney MA,Cosford ND,Jachec C,et al.SIB-1757 and SIB-1893:selective,noncompetitive antagonists of metabotropic glutamate receptor type 5[J].J Pharmacol Exp Ther,1999,290(1):170-181.
[4]Cosford ND,Tehrani L,Roppe J,et al.3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine:a potent and highly selec tive metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity[J].J Med Chem,2003,46(2):204-206.
[5]Felts AS,Saleh SA,Le U,et al.Discovery and SAR of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of m Glu5[J].Bioorg Med Chem Lett,2009,19(23):6623-6626.
[6]石榴,蒋亚琴,白艳秋.代谢型谷氨酸受体5亚型高通量筛选模型的建立[J].中国生物工程杂志,2010,30(5):81-86.
[2]Wu YL,Wang NN,Gu L,et al.The suppressive effect of metabotropic glutamate receptor 5(m Glu5)inhibition on hepa tocarcinogenesis[J].Biochimie,2012,94(11):2366-2375.
[3]Varney MA,Cosford ND,Jachec C,et al.SIB-1757 and SIB-1893:selective,noncompetitive antagonists of metabotropic glutamate receptor type 5[J].J Pharmacol Exp Ther,1999,290(1):170-181.
[4]Cosford ND,Tehrani L,Roppe J,et al.3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine:a potent and highly selec tive metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity[J].J Med Chem,2003,46(2):204-206.
[5]Felts AS,Saleh SA,Le U,et al.Discovery and SAR of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of m Glu5[J].Bioorg Med Chem Lett,2009,19(23):6623-6626.
[6]石榴,蒋亚琴,白艳秋.代谢型谷氨酸受体5亚型高通量筛选模型的建立[J].中国生物工程杂志,2010,30(5):81-86.