Molecular Pharmacology, Vol 20, 295-301, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Identical Antagonist Selectivity of Central and Peripheral Alpha₁-Adrenoceptors

¹ Department of Pharmacy, Division of Pharmacotherapy, University of Amsterdam, 1018 TV Amsterdam, The Netherlands

The present study was undertaken to test the relationship between binding affinity for alpha₁-adrenoceptors and functional antagonism of drug-induced effects mediated by this type of alpha₁-receptor sites for alpha-sympatholytic drugs. The radioligand [³H]prazosin was used to identify alpha₁-adrenoceptors in rat brain membranes. The specific binding of [³H]prazosin was rapid, reversible, saturable, and of high affinity (K_D = 0.21 nM) and involved a single class of binding sites (B_max = 95 fmoles/mg of protein). A variety of alpha-adrenoceptor blocking drugs inhibited the specific binding of [³H]prazosin (0.2 nM) according to sigmoid displacement curves from which the corresponding log IC₅₀ values were calculated. The binding sites of [³H]prazosin in rat cerebral membranes possessed the characteristics of alpha₁-adrenoceptors. Antagonists such as rauwolscine, tolazoline, yohimbine, and piperoxan, known as selective blocking drugs of alpha₂-adrenoceptors, were found to be weak competitors. However, 2-[(2',6'-dimethoxyphenoxyethyl)-aminomethyl]-1,4-benzodioxane (WB-4101) and unlabeled prazosin as well as two of its derivatives, 2-[4-(ethoxyethyloxy)-piperidine-1-yl]-4-amino-6,7-dimethoxyquinazoline (UK-18,596) and 2-[4-(2-(1,4-benzodioxoyl))-piperazine-1-yl]-4-amino-6,7-dimethoxyquinazoline (UK-33,274), which have been classified as antagonists preferably occupying alpha₁-adrenoceptors, strongly interfered with this binding. The same alpha-adrenolytic drugs were studied with respect to their antagonism of (-)-phenylephrine-induced increases in diastolic pressure mediated via vascular, postsynaptic alpha₁-adrenoceptors in pithed, normotensive rats. This antagonism was quantified with the aid of pA₂ values. For the alpha-adrenoceptor antagonists studied (n = 21), the pA₂ in vivo correlated well with the log 1/IC₅₀ (r² = 0.86). Similarly, a close relationship was calculated between the binding data and reported pA₂ values with respect to the antagonism of alpha₁-adrenoceptor-mediated constrictor effects of the rabbit pulmonary artery in vitro (r² = 0.90). The results demonstrate that the binding affinity in vitro of antagonists for alpha₁-adrenoceptors corresponds with their functional antagonism of alpha₁-adrenoceptors in vivo and in vitro. Moreover, these findings point to a similarity among peripheral and central alpha₁-adrenoceptors.

Note:
ACKNOWLEDGMENTS The generous gifts of drugs by Ciba-Geigy, Glaxo, Hoffmann-La Roche, Janssen Pharmaceutica, Organon, Sandoz, Ward Blenkinsop, Wander, Warner, and Wyeth are gratefully acknowledged. The authors are most obliged to Dr. M. J. Davey (Pfizer, Sandwich, Kent, United Kingdom) for providing tritiated and unlabeled prazosin, UK-18,596, and UK-33,274, and to Dr. J. de Boer (University of Amsterdam) for the synthesis of 6-methyl-and 7-chloropiperoxane.

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