Evidence for heterogeneity between pre- and postjunctional alpha-2 adrenoceptors using 9-substituted 3-benzazepines

R. N. Daly, A. C. Sulpizio, B. Levitt, R. M. DeMarinis, J. W. Regan, R. R. Ruffolo, J. P. Hieble

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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 (K(B)) against norepinephrine-induced contraction in the rabbit aorta, correlated with the K(i) value for inhibition of [3H]prazosin binding to central alpha-1 adrenoceptors in rat brain homogenates. Central alpha-2 adrenoceptor affinity, measured as the K(i) 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 K(B) 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 K(i) values for these antagonists against [3H]rauwolscine binding correlate with their K(B) values at the postjunctional alpha-2 adrenoceptors, rather than those at the postjunctional neuroinhibitory alpha-2 adrenoceptor, suggests a pharmacologic similarity between the postjunctional vascular alpha-2 adrenoceptors and the central [3H]rauwolcine binding site. SK&F 104078, the most selective postjunctional vis-a-vis prejunctional alpha-2 adrenoceptor antagonist in the series, inhibited the binding of [3H]yohimbine to human platelet membranes with a K(i) nearly identical to that observed in rat brain, suggesting that the platelet alpha-2 adrenoceptor is also similar to that in the rat brain and canine saphenous vein. The results indicate that selective postjunctional alpha-2 adrenoceptor antagonists may represent novel and useful pharmacologic tools with which to subclassify alpha adrenoceptors.

Original languageEnglish (US)
Pages (from-to)122-128
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - 1988

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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