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Evidence for allosteric blockade of serotonergic receptors in rabbit thoracic aorta

Z Xu and RE Purdy

Department of Pharmacology, Guangdong Medical and Pharmaceutical College, Guangzhou, People's Republic of China.

2-Brom-d-lysergic acid diethylamide (BOL) appeared to behave as either a reversible competitive or noncompetitive antagonist of vascular serotonergic (5-HT2) receptors depending on experimental conditions. This was explored using rabbit thoracic aorta rings mounted in tissue baths for the measurement of isometric contraction. BOL caused concentration-dependent parallel rightward shifts of the 5-HT dose- response curve in untreated aortas but, in addition, caused a marked reduction of maximal response in aortas pretreated with benextramine to inactivate alpha adrenoceptors. Ketanserin behaved as a reversible competitive antagonist in both untreated and benextramine-pretreated aortas. The respective ketanserin pA2 values were 9.08 +/- 0.09 (S.E.M.) and 9.01 +/- 0.04. Ketanserin, 1 x 10(-7) M, reversed completely the reduction of maximal response caused by 1 x 10(-9) M BOL and partially reversed those caused by 1 x 10(-8) and 1 x 10(-7) M BOL. Furthermore, the 5-HT dose-response curve in the presence of 1 x 10(-7) M ketanserin and that in the presence of 1 x 10(-7) M ketanserin plus 1 x 10(-9) M BOL were superimposed. These results are consistent with the conclusion that BOL is a noncompetitive 5-HT2 receptor antagonist. We propose that BOL acts at an allosteric site to convert the 5-HT2 receptor to a low activity state, thus, reducing the maximal response. BOL does not act at the 5-HT2 receptor itself. Ketanserin competes with 5-HT at the 5-HT2 receptor and with BOL at the allosteric site.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 248, Issue 3, pp. 1091-1095, 03/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics




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 Proc. Natl. Acad. Sci. USAHome page
E. A. Thomas, M. J. Carson, M. J. Neal, and J. G. Sutcliffe
Unique allosteric regulation of 5-hydroxytryptamine receptor-mediated signal transduction by oleamide
PNAS, December 9, 1997; 94(25): 14115 - 14119.
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Copyright © 1989 by the American Society for Pharmacology and Experimental Therapeutics.