ABSTRACT
We have recently reported the synthesis and alpha 2-antagonist activity of the methoxy derivative 2 [2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline] and described the enhanced potency of this compound over the parent 1,4-benzodioxan, idazoxan, in reversing the inhibition caused by alpha 2-adrenoreceptor agonists of the electrically induced twitch in the rat or mouse vas deferens. It was of interest to us to discover whether a similar substitution in the structurally related alpha 2-adrenoreceptor antagonists piperoxan, prosympal, and fenmetazole would similarly enhance potency. We subsequently discovered that this was not so and potency was decreased markedly. In particular, that of the methoxy derivative of piperoxan was ca. 220 times less than the parent structure.
Subject(s)
Adrenergic alpha-Antagonists/pharmacology , Dioxanes/pharmacology , Dioxins/pharmacology , Imidazoles/pharmacology , Piperidines/pharmacology , Piperoxan/pharmacology , Animals , Chemical Phenomena , Chemistry , Clonidine/antagonists & inhibitors , Male , Mice , Muscle Contraction/drug effects , Phenylephrine/antagonists & inhibitors , Rats , Rats, Inbred Strains , Receptors, Adrenergic, alpha/drug effects , Receptors, Adrenergic, alpha/physiology , Structure-Activity RelationshipABSTRACT
The synthesis and pharmacological activity of a series of 2-substituted derivatives of the selective alpha 2-adrenoreceptor antagonist idazoxan (RX 781094) is described. Substitution in this position by alkyl, alkenyl, cycloalkenyl, and alkoxy groups in many cases gives compounds whose potencies and selectivities are significantly greater than those of the parent compound.
