Towart R, Sautel M, Moret E, Costa E, Theraulaz M, Weitsch A F
OTA, Innovation Department, Nyon, Switzerland.
Agents Actions Suppl. 1991;33:403-8. doi: 10.1007/978-3-0348-7309-3_30.
Dimethindene maleate (DM) (= Fenistil) is a potent antihistamine with a prolonged duration of action. On the histamine-stimulated guinea-pig ileum DM has a pA2 of 9.3 but produces a very marked depression of the maximum response at 10(-8) M. DM has no effect on H2 receptors nor on H3 receptors, and is not a calcium channel blocker. Muscarinic receptors (carbachol-stimulated ileum) were only influenced (competitively) at 10(-7) M or above, suggesting that the non-competitive effects described above could be due to a specific reaction with the histamine H1 receptor. As non-specific effects, such as membrane-stabilisation, would normally be seen with both isomers equally, we studied the effects of the optical isomers of DM. The (-) isomer had a profile identical to that of DM, but was slightly more potent. The (+) isomer was some 30 times less potent (results confirmed by binding studies). However in contrast to DM and the (-) isomer, the (+) isomer showed a "classical" antagonism, pA2 = 7.7, with no evidence of non-competitive effects. Thus the more active (-) isomer of DM has a potent, non-competitive H1 histamine antagonist effect. The relevance of these findings to DM's clinical profile is discussed.
马来酸氯苯那敏（DM）（= 非尼腊明）是一种作用时间延长的强效抗组胺药。在组胺刺激的豚鼠回肠上，DM的pA2为9.3，但在10^(-8) M时会使最大反应产生非常明显的抑制。DM对H2受体和H3受体均无作用，也不是钙通道阻滞剂。毒蕈碱受体（卡巴胆碱刺激的回肠）仅在10^(-7) M或更高浓度时受到（竞争性）影响，这表明上述非竞争性作用可能是由于与组胺H1受体的特异性反应所致。由于非特异性作用，如膜稳定作用，通常在两种异构体中均同等可见，因此我们研究了DM的旋光异构体的作用。（-）异构体的作用特征与DM相同，但效力稍强。（+）异构体的效力约低30倍（结合研究证实了结果）。然而，与DM和（-）异构体不同，（+）异构体表现出“经典”拮抗作用，pA2 = 7.7，没有非竞争性作用的证据。因此，DM的活性更强的（-）异构体具有强效的、非竞争性的H1组胺拮抗作用。讨论了这些发现与DM临床特征的相关性。
