Molecular Pharmacology, Vol 9, 1-9, Copyright © 1973 by the American Society for Pharmacology and Experimental Therapeutics

On the Analysis of Pharmacological Experiments in Terms of an Allosteric Receptor Model

¹ Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755

According to the usual drug-receptor model, developed by Clark, Gaddum, and Stephenson, one can determine drug-receptor dissociation equilibriun constants and relative efficacies experimentally, by analyzing the drug concentrations which cause equal responses under various conditions. Underlying this analysis is the concept of the "stimulus," which is directly proportional to the fraction of receptors activated the proportionality constant being characteristic of each drug, and being known as the "efficacy." Equal biological responses are assumed to correspond to equal stimuli. Such experiments to determine equieffective drug concentrations circumvent the problem presented by the fact that there is no generally valid theory to interpret the shapes of concentration-response curves. This paper discusses the interpretation of these experiments according to the allosteric receptor model proposed by Karlin. In this model the receptor is assumed to have two conformational states, R and T, normally present in the ratio T/R = L. A drug A is assumed to combine reversibly with each of these two forms, with dissociation equilibrium constants K_AR and K_AT, respectively, and the biological response is assumed to depend on the proportion of receptors in the R form. The present analysis shows that for competitive drug interactions a "stimulus" can be defined which has exactly the same algebraic form as the "stimulus" in the Clark-Gaddum-Stephenson model; hence the two models are experimentally indistinguishable with respect to competitive drug interactions. The drug-receptor dissociation constant determined by these methods is K_AT, and the "efficacy" depend-on the relative affinities of the drug for the R and T forms; i.e., the "efficacy" is K_AT/K_AR-1.

On the other hand, the experimental method utilizing partial irreversible receptor inactivation yields a different apparent dissociation constant, namely, [K_AT^-1 + (K_ARL)^-1]^-1. By doing different kinds of experiments on two or more drugs, one can in principle determine all the equilibrium constants in the allosteric model. Both models allow for the possibilities of negative efficacy and of nonparallel log concentration-response curves for competitive antagonists with nonzero efficacy. Experimental evidence to date does not clearly rule out either model.

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