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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 alpha 2- and postjunctional alpha 1-adrenoceptor antagonist potencies were assessed by determining pA2 values against clonidine on the stimulated rat was deferens and noradrenaline on the anococcygeus muscle, respectively. The rank order of prejunctional alpha 2-adrenoceptor antagonist potency was idazoxan greater than yohimbine greater than rauwolscine much greater than corynanthine. At postjunctional alpha 1-adrenoceptors the rank order of antagonist potency was rauwolscine greater than corynanthine greater than yohimbine greater than idazoxan. The selectivity values (alpha 2/alpha 1) 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 (alpha 2) and 3H-prazosin (alpha 1) 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Appropriate modification of 14 beta-methoxy- and 14 beta-ethoxycodeinone (prepared by alkylation of 14 beta-hydroxycodeinone) has generated four alkoxy analogues (3a-d) of naloxone and naltrexone. These agents were pure narcotic antagonists in contradiction to the predictions of the common anionic receptor site hypothesis, postulated to be of importance in the enhanced antagonism of naloxone. The molecular change from allyl to cyclopropylmethyl on the N atom increased selectivity of these antagonists for the mu receptor to the same extent as found for naloxone. Increase in the length of the C14 O-substituent had no effect on receptor selectivity, and either formation in most cases did not significantly alter oral/parenteral ratios of durations of action.

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