Abstract

A series of alpha adrenoceptor antagonists, including both reference compounds and the novel benzazepine antagonists, SK&F 86466 (6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine) and two of its 9-substituted derivatives, SK&F 101253 and SK&F 104078, were tested in vitro for affinity at central and peripheral alpha adrenoceptor subtypes. Peripheral alpha-1 adrenoceptor antagonist potency of these agents, as assessed by the receptor dissociation constant (KB) against norepinephrine-induced contraction in the rabbit aorta, correlated with the Ki value for inhibition of [3H]prazosin binding to central alpha-1 adrenoceptors in rat brain homogenates. Central alpha-2 adrenoceptor affinity, measured as the Ki for inhibition of [3H]rauwolscine binding to rat brain homogenates, correlated well with antagonist activity at peripheral postjunctional alpha-2 adrenoceptors as reflected by the KB against B-HT 920-induced contraction in canine saphenous vein. The 9-substituted benzazepines, SK&F 101253 and SK&F 104078, produce preferential blockade of postjunctional vs. prejunctional alpha-2 adrenoceptors in peripheral models. The high affinity of SK&F 104078 for postjunctional alpha-2 adrenoceptors in the canine saphenous vein was confirmed by its ability to inhibit [3H]rauwolscine binding to postjunctional alpha-2 adrenoceptors in this tissue. The observation that the Ki values for these antagonists against [3H] rauwolscine binding correlate with their KB values at the postjunctional alpha-2 adrenoceptors, rather than those at the prejunctional neuroinhibitory alpha-2 adrenoceptor, suggests a pharmacologic similarity between the postjunctional vascular alpha-2 adrenoceptors and the central [3H]rauwolscine binding site.(ABSTRACT TRUNCATED AT 250 WORDS)