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.
OTA, Innovation Department, Nyon, Switzerland.
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Towart
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Sautel
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Moret
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Costa
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Theraulaz
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Weitsch
D000818:Animals; D016275:Atrial Function; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004115:Dimethindene / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D017446:Impromidine; D009119:Muscle Contraction / Q000187:drug effects; D011968:Receptors, Histamine / Q000187:drug effects / Q000502:physiology; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000502:physiology; D011970:Receptors, Histamine H2 / Q000187:drug effects / Q000502:physiology; D018100:Receptors, Histamine H3; D013237:Stereoisomerism
D006146:Guanidines; D006634:Histamine H1 Antagonists; D007093:Imidazoles; D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; D004115:Dimethindene; D006632:Histamine; D002217:Carbachol; D017446:Impromidine