Differential blockade of pre- and postsynaptic alpha-adrenoceptors by the 2-R and 2-S enantiomers of WB4101.
Agonists and antagonists of the alpha-adrenoceptor have been shown to possess different degrees of potency at the pre- and postsynaptic levels. The present investigation was undertaken to see whether the two optical isomers of WB4101 likewise exhibit differential blockade at the two receptor sites. This was achieved by measuring the potencies of 2-R and 2-S WB4101 against noradrenaline-induced contractions of the rat isolated vas deferens and against clonidine-induced inhibition of the twitch response in field stimulated rat vas deferens. Results showed that though the enantiomers exhibited widely differing potency, as indicated by calculations of pA2 values, at the postsynaptic level, they possessed almost identical potency presynaptically. In addition, 2-aminomethyl-1,4-benzodioxan itself both exhibited reasonable presynaptic alpha-adrenoceptor blocking activity, whilst being devoid of activity postsynaptically. The values for slope on the Schild plots for 2-R and 2-S WB4101 indicated that they produced classical competitive antagonism at the postsynaptic receptor but at the presynaptic level the values for slope were indicative of a non-competitive type of blockade. Results are discussed in terms of recent suggestions of that agonists and antagonists of the alpha-adrenoceptor may not share a common mechanism or site of action at the presynaptic level.
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D004146:Dioxanes / Q000494:pharmacology*; D004147:Dioxins / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011941:Receptors, Adrenergic / Q000187:drug effects*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D013237:Stereoisomerism; D014649:Vas Deferens / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D004147:Dioxins; D011941:Receptors, Adrenergic; D011942:Receptors, Adrenergic, alpha; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane