Alpha-adrenoceptor blocking properties of vesamicol.
The side-effects of vesamicol, an inhibitor of acetylcholine storage, on alpha 1- and alpha 2-adrenoceptors have been studied in the isolated rat vas deferens. Antagonism of alpha 1-adrenoceptors was determined from the ability of vesamicol to reduce contractions elicited by exogenous noradrenaline. Antagonism of alpha 2-adrenoceptors was determined from the ability of vesamicol to block the inhibitory effects of the alpha 2-adrenoceptor agonist clonidine on electrically evoked twitches. In the absence of noradrenaline uptake block, (-)-vesamicol, the isomer active at cholinergic synapses, produced a leftward shift of the noradrenaline concentration-effect curve. This effect was abolished by desipramine suggesting that it is due to an ability of (-)-vesamicol to block uptake1. In the presence of noradrenaline uptake blockers, (-)-vesamicol produced a competitive, non-selective block of both alpha 1- and alpha 2-adrenoceptors with a Kd of around 40 microM (pA2 4.4). (+)-Vesamicol, the isomer that has no activity at cholinergic synapses, was equipotent with the (-)-isomer for blocking alpha 2-adrenoceptors. In addition to its alpha-adrenoceptor antagonist activity, (-)-vesamicol augmented the maximum response of the tissue to exogenous and endogenous noradrenaline. This study was unable to determine the exact nature of this effect. We suggest that the alpha-adrenoceptor blocking activity of vesamicol is a function of the phenylpiperidino moiety of the molecule.
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland, U.K.
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D000317:Adrenergic alpha-Antagonists; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D003345:Corticosterone / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004558:Electric Stimulation; D019329:Idazoxan; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D013237:Stereoisomerism; D014649:Vas Deferens / Q000187:drug effects* / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D010880:Piperidines; D011942:Receptors, Adrenergic, alpha; C006189:vesamicol; D003000:Clonidine; D003891:Desipramine; D003345:Corticosterone; D009638:Norepinephrine; D019329:Idazoxan