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

Abstract

1 The selectivity and specificity of RX 781094 [2-(2-(1,4 benzodioxanyl))2-imidazoline HCl] for α-adrenoceptors have been examined in peripheral tissues. 2 In isolated tissue experiments RX 781094 was a competitive antagonist at prejunctional α₂-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 α₁-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 α₂/α₁-adrenoceptor selectivity ratio for RX 781094 was 288. 4 The rank order of α₂/α₁-adrenoceptor selectivities for the antagonists studied was RX 781094 > RS 21361 > yohimbine > piperoxan > phentolamine > WB 4101 > prazosin. 5 RX 781094 had extremely low affinity for β-adrenoceptors, histamine receptors, cholinoceptors, 5-hydroxytryptamine and opiate receptors in vitro. 6 In pithed rats, intravenous administration of RX 781094 antagonized the prejunctional α₂-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 α₂-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. 8 In the pithed rat, RX 781094 preferentially antagonized the pressor responses evoked by postjunctional α₂-adrenoceptor activation by UK 14,304 although higher doses also inhibited the effects of phenylephrine and cirazoline at postjunctional α₁-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 α₂-adrenoceptor antagonist with a high degree of specificity for these receptors.