Studies on RX 781094: a selective, potent and specific antagonist of α2‐adrenoceptors

Abstract

The selectivity and specificity of RX 781094 [2‐(2‐(1,4 benzodioxanyl))2‐imidazoline HCl] for α‐adrenoceptors have been examined in peripheral tissues. In isolated tissue experiments RX 781094 was a competitive antagonist at prejunctional α 2‐adrenoceptors situated on the sympathetic nerve terminals of the rat (pA 2 = 8.56) and mouse (pA 2 = 7.93) vas deferens and on the parasympathetic nerve terminals of the guinea‐pig ileum (pA 2 = 8.55). Although RX 781094 was also a competitive antagonist at the postjunctional α 1‐adrenoceptors of the rat anococcygeus muscle (pA 2 = 6.10) its affinity for these receptors was markedly less than that displayed for prejunctional sites. From pA 2 values obtained in the rat vas deferens and anococcygeus muscle the calculated α 2/α 1‐adrenoceptor selectivity ratio for RX 781094 was 288. The rank order of α 2/α 1‐adrenoceptor selectivities for the antagonists studied was RX 781094 > RS 21361 > yohimbine > piperoxan > phentolamine > WB 4101 > prazosin. RX 781094 had extremely low affinity for β‐adrenoceptors, histamine receptors, cholinoceptors, 5‐hydroxytryptamine and opiate receptors in vitro. In pithed rats, intravenous administration of RX 781094 antagonized the prejunctional α 2‐adrenoceptor agonist effects of clonidine and guanabenz on electrically‐induced contractions of the vas deferens and anococcygeus muscle respectively. In the vas deferens the rank order of α 2‐adrenoceptor antagonist potencies was RX 781094 > phentolamine > piperoxan > yohimbine > RS 21361 > WB 4101. Only RX 781094, yohimbine and RS 21361 were active against guanabenz in the anococcygeus muscle. In the pithed rat, RX 781094 preferentially antagonized the pressor responses evoked by postjunctional α 2‐adrenoceptor activation by UK 14,304 although higher doses also inhibited the effects of phenylephrine and cirazoline at postjunctional α 1‐adrenoceptors. RX 781094 had little effect on the cardiovascular responses to 5‐hydroxytryptramine, angiotensin II, histamine, acetylcholine and isoprenaline in pithed rats and rats anaesthetized with pentobarbitone. These results demonstrate that RX 781094 is a potent and selective α 2‐adrenoceptor antagonist with a high degree of specificity for these receptors.