Ginap T, Dooley D J, Feuerstein T J
Department of Neuroscience, Purke-Davis Pharmaceutical Research, Warner-Lambert Co., Ann Arbor, MI 48106-1047.
Neurosci Lett. 1993 Jun 25;156(1-2):35-8. doi: 10.1016/0304-3940(93)90433-l.
The non-dihydropyridine FPL 64176 (methyl-2,5-dimethyl-4-(2-phenylmethyl)benzoyl-[1-H]pyrrole-3-carboxy la te) was tested for an interaction with neuronal L-type voltage-sensitive calcium channels (L-VSCCs) by using a [3H]isradipine ([3H]ISR) binding assay, and for its ability to enhance K(+)-evoked [3H]norepinephrine ([3H]NE) release from rat neocortical slices. The classical L-VSCC activator, the dihydropyridine (DHP) BAY K 8644, was also used for comparative purposes. FPL 64176 and BAY K 8644 both produced a similar concentration-dependent enhancement of 15 mM K(+)-evoked [3H]NE release which could be completely blocked by the L-VSCC blocker ISR (0.1 microM). FPL 64176, in contrast to BAY K 8644, was a very weak inhibitor of [3H]ISR binding to L-VSCCs. These findings indicate that FPL 64176 is a novel non-dihydropyridine L-VSCC activator, most probably by acting on a site different from the DHP binding site.
通过使用[3H]异搏定（[3H]ISR）结合试验，对非二氢吡啶类药物FPL 64176（2,5 - 二甲基 - 4 - （2 - 苯甲基）苯甲酰基 - [1 - H]吡咯 - 3 - 羧酸甲酯）与神经元L型电压敏感性钙通道（L - VSCCs）的相互作用进行了测试，并检测了其增强K(+)诱发的[3H]去甲肾上腺素（[3H]NE）从大鼠新皮质切片释放的能力。经典的L - VSCC激活剂二氢吡啶类（DHP）BAY K 8644也用于对比。FPL 64176和BAY K 8644均产生了相似的浓度依赖性增强作用，使15 mM K(+)诱发的[3H]NE释放增加，且这种增强作用可被L - VSCC阻滞剂ISR（0.1 microM）完全阻断。与BAY K 8644不同，FPL 64176是[3H]ISR与L - VSCCs结合的非常弱的抑制剂。这些发现表明，FPL 64176是一种新型的非二氢吡啶类L - VSCC激活剂，很可能是通过作用于与DHP结合位点不同的位点发挥作用。
