Highly selective and specific antagonism of central and peripheral alpha 2-adrenoceptors by atipamezole.

The potency, selectivity and specificity of atipamezole [MPV-1248, 4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole], as an alpha 2-adrenoceptor antagonist was studied. In receptor binding studies [( 3H]-clonidine and [3H]-prazosin displacement) an alpha 2/alpha 1 selectivity ratio of 8526 was obtained for atipamezole, while idazoxan and yohimbine showed ratios of 27 and 40, respectively. Atipamezole had also about a 100 times higher affinity on alpha 2-adrenoceptors than the reference compounds. In the electrically stimulated prostatic portion of rat vas deferens, atipamezole showed potent competitive antagonistic activity against clonidine (pA2 8.6) and medetomidine (pA2 8.7) at presynaptic alpha 2-adrenoceptors. In the epididymal portion of the rat vas deferens, atipamezole had only weak competitive antagonistic activity against phenylephrine (pA2 5.0). In binding studies and studies with isolated organs, atipamezole had no effect on beta 1-, beta 2-, H1-, H2-, 5-HT1-, 5-HT2-, muscarine, DA2-, tryptamine, GABA, opiate and benzodiazepine receptors. In the pithed rat, atipamezole, like idazoxan, had partial alpha 1-adrenoceptor-mediated vasoconstrictor effects in addition to potent alpha 2-adrenoceptor blocking activity. In mice, medetomidine-induced sedation was effectively antagonized by atipamezole. These results show that atipamezole is a potent, selective and specific antagonist of both centrally and peripherally located alpha 2-adrenoceptors.