Comparison of the ?-adrenoceptor antagonist profiles of idazoxan (RX 781094), yohimbine, rauwolscine and corynanthine

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Abstract
In the present studies the potency and selectivity of idazoxan (RX 781094) were compared with yohimbine and its diastereoisomers rauwolscine and corynanthine in both functional studies and radioligand binding experiments. Prejunctional α2- and postjunctional α1-adrenoceptor antagonist potencies were assessed by determining pA2 values against clonidine on the stimulated rat vas deferens and noradrenaline on the anococcygeus muscle, respectively. The rank order of prejunctional α2-adrenoceptor antagonist potency was idazoxan > yohimbine > rauwolscine ≫ corynanthine. At postjunctional α1-adrenoceptors the rank order of antagonist potency was rauwolscine > corynanthine > yohimbine > idazoxan. The selectivity values (α2/α1) for idazoxan, yohimbine, rauwolscine and corynanthine were 245, 45, 3 and 0.03 respectively. The selectivity and potency profiles established for these antagonists in functional studies were confirmed in radioligand binding studies utilising 3H-idazoxan (α2) and 3H-prazosin (α1) in rat cerebral cortex. In pithed rats intravenously administered idazoxan, yohimbine and rauwolscine fully reversed the inhibitory effects of clonidine on electrically-induced contractions of the vas deferens; idazoxan was approximately ten times more potent than both yohimbine and rauwolscine. Corynanthine was inactive. Idazoxan and yohimbine also fully antagonised the inhibitory effects of guanabenz on electrically-induced contractions of the anococcygeus muscle; idazoxan again was more than ten times more potent than yohimbine in this model. The inhibitory effects of guanabenz were less readily antagonised by rauwolscine indicating that the selectivity of this compound is less than that of yohimbine in this tissue. Corynanthine was again inactive. Studies were also undertaken in which the effects of an extended range of antagonists were examined on contractions of the anococcygeus muscle induced either by electrical stimulation or intra-arterial phenylphrine. Selective α1-adrenoceptor antagonists produced a parallel block of the effects of stimulation and phenylephrine indicating that the postjunctional receptor in this tissue is predominantly α1- character. In this tissue idazoxan potentiated nerve stimulation without inhibiting phenylephrine responses; of the compounds studied only idazoxan failed to influence phenylephrine responses. Under the present experimental conditions idazoxan only produced antagonist properties at α-adrenoceptors and consistently displayed improved α2-selectivity and potency with respect to yohimbine and rauwolscine.