Miri R, Howlett S E, Knaus E E
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Arch Pharm (Weinheim). 1997 Oct;330(9-10):290-4. doi: 10.1002/ardp.19973300905.
A group of racemic isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(thienyl)-5-pyridinecarboxylates++ + 7a-f were prepared using a modified Hantzsch reaction that involved the condensation of a thienylcarboxaldehyde 4a-f with isopropyl 3-aminocrotonate 5 and nitroacetone 6. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay. Compounds 7a-f exhibited weaker calcium channel antagonist activity (IC50 = 10(-5) to 10(-7) M range) than the reference drug nifedipine (IC50 = 1.43 x 10(-8) M). The point of attachment of the C-4 thienyl ring system was a determinant of antagonist activity [3-thienyl (7b) > 2-thienyl (7a)]. A 5-substituent in the 2-thienyl moiety influenced antagonist activity where the potency order was 5-bromo-2-thienyl 7f > or = 5-methyl-2-thienyl 7c > 2-thienyl 7a. Although the 5-methyl-2-thienyl 7c and 3-methyl-2-thienyl 7d isomers are equipotent antagonists, the 5-bromo-2-thienyl compound 7f appears to be marginally more active than the 4-bromo-2-thienyl isomer 7e. The 2-thienyl compound 7a, unlike the 3-thienyl isomer 7b, exhibited an agonist effect on GPILSM in the absence of the muscarinic agonist carbachol. Effects of the 2-thienyl 7a and 3-thienyl 7b isomers on the magnitude of calcium current were determined in guinea pig ventricular myocytes with voltage clamp techniques. Results showed that 2-thienyl 7a inhibited calcium current (antagonist) when voltage steps were made from a potential of -40 mV. However, when voltage steps were made from -60 mV, 7a enhanced calcium current (agonist). The 3-thienyl isomer 7b had little, if any, effect on calcium current.
使用改良的汉茨施反应制备了一组外消旋的异丙基 1,4-二氢-2,6-二甲基-3-硝基-4-(噻吩基)-5-吡啶羧酸酯 7a - f，该反应涉及噻吩基甲醛 4a - f 与异丙基 3-氨基巴豆酸酯 5 和硝基丙酮 6 的缩合。使用豚鼠回肠纵行平滑肌（GPILSM）试验测定体外钙通道拮抗剂活性。化合物 7a - f 表现出比参考药物硝苯地平（IC50 = 1.43×10(-8) M）弱的钙通道拮抗剂活性（IC50 在 10(-5) 至 10(-7) M 范围内）。C - 4 噻吩环系统的连接点是拮抗剂活性的一个决定因素[3 - 噻吩基（7b）> 2 - 噻吩基（7a）]。2 - 噻吩基部分的 5 - 取代基影响拮抗剂活性，其效价顺序为 5 - 溴 - 2 - 噻吩基 7f ≥ 5 - 甲基 - 2 - 噻吩基 7c > 2 - 噻吩基 7a。尽管 5 - 甲基 - 2 - 噻吩基 7c 和 3 - 甲基 - 2 - 噻吩基 7d 异构体是等效的拮抗剂，但 5 - 溴 - 2 - 噻吩基化合物 7f 似乎比 4 - 溴 - 2 - 噻吩基异构体 7e 活性略高。与 3 - 噻吩基异构体 7b 不同，2 - 噻吩基化合物 7a 在没有毒蕈碱激动剂卡巴胆碱的情况下对 GPILSM 表现出激动剂作用。使用电压钳技术在豚鼠心室肌细胞中测定了 2 - 噻吩基 7a 和 3 - 噻吩基 7b 异构体对钙电流幅度的影响。结果表明，当电压阶跃从 - 40 mV 的电位开始时，2 - 噻吩基 7a 抑制钙电流（拮抗剂）。然而，当电压阶跃从 - 60 mV 开始时，7a 增强钙电流（激动剂）。3 - 噻吩基异构体 7b 对钙电流几乎没有影响（如果有影响的话也很小）。
