Investigation of the antihistaminic action of dimethindene maleate (Fenistil) and its optical isomers.

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.