Selective alpha-2 adrenoceptor blockade by SK&F 86466: in vitro characterization of receptor selectivity.

SK&F 86466 (6-chloro-N-methyl-2,3,4,5-tetrahydro-1-H-3-benzazepine) is a potent and selective antagonist at alpha-2 adrenoceptors. Prejunctional alpha-2 adrenoceptor antagonism can be demonstrated either by blockade of the alpha-2 adrenoceptor-mediated neuroinhibitory effect of clonidine or B-HT 920 in the guinea-pig atrium [receptor dissociation constant (KB) = 13-17 nM] or by potentiation of nerve-evoked release of [3H]norepinephrine from prelabeled guinea-pig atria, dog splenic artery or rabbit ear artery. Blockade of the postjunctional alpha-2 adrenoceptor was also seen, as demonstrated by a parallel shift to the right of the concentration-response curve for B-HT 920 as a constrictor agent in the dog saphenous vein. The KB for SK&F 86466 in this test system was 42 nM. The affinity of SK&F 86466 for the alpha-1 adrenoceptor is much lower, with a KB of 900 nM against norepinephrine-mediated constriction in the rabbit ear artery, or 1100 nM vs. SK&F 89748-induced constriction in the dog saphenous vein. The alpha-2/alpha-1 adrenoceptor selectivity ratio of SK&F 86466 is comparable to that obtained with agents such as yohimbine, making SK&F 86466 a useful tool for characterization of alpha-2 adrenoceptors and for investigation of their physiological role.