Studies on RX 781094: a selective, potent and specific antagonist of alpha 2-adrenoceptors.

1 The selectivity and specificity of RX 781094 [2-(2-(1,4 benzodioxanyl))2-imidazoline HCl] for alpha-adrenoceptors have been examined in peripheral tissues. 2 In isolated tissue experiments RX 781094 was a competitive antagonist at prejunctional alpha 2-adrenoceptors situated on the sympathetic nerve terminals of the rat (pA2 = 8.56) and mouse (pA2 = 7.93) vas deferens and on the parasympathetic nerve terminals of the guinea-pig ileum (pA2 = 8.55). 3 Although RX 781094 was also a competitive antagonist at the postjunctional alpha 1-adrenoceptors of the rat anococcygeus muscle (pA2 = 6.10) its affinity for these receptors was markedly less than that displayed for prejunctional sites. From pA2 values obtained in the rat vas deferens and anococcygeus muscle the calculated alpha 2/alpha 1-adrenoceptor selectivity ratio for RX 781094 was 288. 4 The rank order of alpha 2/alpha 1-adrenoceptor selectivities for the antagonists studied was RX 781094 greater than RS 21361 greater than yohimbine greater than piperoxan greater than phentolamine greater than WB 4101 greater than prazosin. 5 RX 781094 had extremely low affinity for beta-adrenoceptors, histamine receptors, cholinoceptors, 5-hydroxytryptamine and opiate receptors in vitro. 6 In pithed rats, intravenous administration of RX 781094 antagonized the prejunctional alpha 2-adrenoceptor agonist effects of clonidine and guanabenz on electrically-induced contractions of the vas deferens and anococcygeus muscle respectively. 7 In the vas deferens the rank order of alpha 2-adrenoceptor antagonist potencies was RX 781094 greater than phentolamine greater than piperoxan greater than yohimbine greater than RS 21361 greater than WB 4101. Only RX 781094, yohimbine and RS 21361 were active against guanabenz in the anococcygeus muscle. 8 In the pithed rat, RX 781094 preferentially antagonized the pressor responses evoked by postjunctional alpha 2-adrenoceptor activation by UK 14,304 although higher doses also inhibited the effects of phenylephrine and cirazoline at postjunctional alpha 1-adrenoceptors. 9 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. 10 These results demonstrate that RX 781094 is a potent and selective alpha 2-adrenoceptor antagonist with a high degree of specificity for these receptors.