TY - JOUR T1 - Identical Antagonist Selectivity of Central and Peripheral <em>Alpha</em><sub>1</sub>-Adrenoceptors JF - Molecular Pharmacology JO - Mol Pharmacol SP - 295 LP - 301 VL - 20 IS - 2 AU - P. B. M. W. M. TIMMERMANS AU - F. KARAMAT ALI AU - H. Y. KWA AU - A. M. C. SCHOOP AU - F. P. SLOTHORST-GRISDIJK AU - P. A. VAN ZWIETEN Y1 - 1981/09/01 UR - http://molpharm.aspetjournals.org/content/20/2/295.abstract N2 - 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 (KD = 0.21 nM) and involved a single class of binding sites (Bmax = 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. 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. ER -