Identical Antagonist Selectivity of Central and Peripheral Alpha1-Adrenoceptors

• Published in: Molecular pharmacology Vol. 20; no. 2; p. 295
• Main Authors: P. B. M. W. M. TIMMERMANS, F. KARAMAT ALI, H. Y. KWA, A. M. C. SCHOOP, F. P. SLOTHORST-GRISDIJK, P. A. VAN ZWIETEN
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.09.1981
• ISSN: 0026-895X; 1521-0111

The present study was undertaken to test the relationship between binding affinity for alpha 1 -adrenoceptors and functional antagonism of drug-induced effects mediated by this type of alpha 1 -receptor sites for alpha -sympatholytic drugs. The radioligand [ 3 H]prazosin was used to identify alpha 1 -adrenoceptors in rat brain membranes. The specific binding of [ 3 H]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 [ 3 H]prazosin (0.2 nM) according to sigmoid displacement curves from which the corresponding log IC 50 values were calculated. The binding sites of [ 3 H]prazosin in rat cerebral membranes possessed the characteristics of alpha 1 -adrenoceptors. Antagonists such as rauwolscine, tolazoline, yohimbine, and piperoxan, known as selective blocking drugs of alpha 2 -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 alpha 1 -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 alpha 1 -adrenoceptors in pithed, normotensive rats. This antagonism was quantified with the aid of pA 2 values. For the alpha -adrenoceptor antagonists studied ( n = 21), the pA 2 in vivo correlated well with the log 1/IC 50 ( r 2 = 0.86). Similarly, a close relationship was calculated between the binding data and reported pA 2 values with respect to the antagonism of alpha 1 -adrenoceptor-mediated constrictor effects of the rabbit pulmonary artery in vitro ( r 2 = 0.90). The results demonstrate that the binding affinity in vitro of antagonists for alpha 1 -adrenoceptors corresponds with their functional antagonism of alpha 1 -adrenoceptors in vivo and in vitro . Moreover, these findings point to a similarity among peripheral and central alpha 1 -adrenoceptors.