Baxter A J, Dixon J, Ince F, Manners C N, Teague S J
Department of Medicinal Chemistry, Fisons plc, Loughborough, Leicestershire, United Kingdom.
J Med Chem. 1993 Sep 17;36(19):2739-44. doi: 10.1021/jm00071a004.
Methyl 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate, FPL 64176 (1), is the first example of a new class of calcium channel activator (CCA) that does not act on any of the well-defined calcium channel modulator receptor sites, as typified by verapamil, diltiazem, and the dihydropyridines. The potent activity of 1, having the 2-(phenylmethyl)benzoyl substituent, was predicted using QSAR on an initial set of less potent benzoylpyrroles. When compared to the CCA Bay K 8644, 1 has similar potency on calcium uptake into GH3 cells (both have EC50 approximately 0.015 microM) but is appreciably more potent functionally at increasing contractility in a guinea pig atria preparation (1 has EC50 = 0.049 microM vs Bay K 8644 EC50 = 1.95 microM). 1 is an achiral, pharmacologically clean agonist with no demonstrable partial agonist properties and possesses appreciably higher efficacy than Bay K 8644. It should therefore become a useful biochemical and pharmacological tool for the study of calcium channels in many cell types.
2,5 - 二甲基 - 4 - [2 - (苯甲基)苯甲酰基]-1H - 吡咯 - 3 - 羧酸甲酯，FPL 64176 (1)，是一类新型钙通道激活剂（CCA）中的首个实例，它不像维拉帕米、地尔硫䓬和二氢吡啶那样作用于任何明确的钙通道调节剂受体位点。1具有2 - (苯甲基)苯甲酰基取代基，其强效活性是通过对一组活性较弱的苯甲酰基吡咯进行定量构效关系（QSAR）预测得到的。与CCA Bay K 8644相比，1在促进GH3细胞摄取钙方面具有相似的效力（二者的半数有效浓度（EC50）均约为0.015微摩尔），但在豚鼠心房标本中增强收缩力方面，1的功能效力明显更强（1的EC50 = 0.049微摩尔，而Bay K 8644的EC50 = 1.95微摩尔）。1是一种非手性、药理性质纯净的激动剂，没有可证明的部分激动剂特性，并且比Bay K 8644具有明显更高的效能。因此，它应该会成为研究多种细胞类型中钙通道的一种有用的生化和药理学工具。
