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On the use of functional antagonism to estimate dissociation constants for beta adrenergic receptor agonists in isolated guinea-pig trachea

CK Buckner and RK Saini

In guinea-pig trachea, the maximum degree of relaxation that can be elicited by beta adrenergic receptor agonists depends upon the degree of contraction of the smooth muscle induced by cholinergic agonists. In these studies, it is shown that increasing concentrations of carbamylcholine (carbachol) result in a shift to the right of the dose- response curves to (-)-isoproterenol and (-)-soterenol and a reduction of the maximum degree of relaxation produced by these agonists relative to that produced by papaverine. Soterenol is demonstrated to be a partial agonist relative to isoproterenol since its maximum response is reduced to a greater extent by carbachol and it displaces the carbachol dose-response curves to the right less than does isoproterenol. The data were used to calculate, by three different theoretical models of drug-receptor interactions, a dissociation constant (KA) for soterenol. All values obtained were within 2-fold differences. The range of KA values for soterenol was from 5.4 to 9.6 times 10(-8) M. These values are about 100 times larger than the ED50 value for soterenol obtained in the absence of carbachol. The KA value estimated for (-)- isoproterenol (about 3 times 10(-8) M) by one of the models is also around 100 times larger than its ED50 value. This demonstrates further that ED50 values are unreliable indicators of the affinities of agonists for receptors.

Volume 194, Issue 3, pp. 565-574, 09/01/1975
Copyright © 1975 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics.