Potential errors in agonist dissociation constant estimation caused by desensitization.
A simple model of receptor desensitization is developed and analysed to predict the consequences of acute receptor loss on the pharmacological quantification of agonist action. The model incorporates the desensitization scheme of Katz and co-workers (1957) into the operational model of agonism (Black & Leff, 1983) and, therefore, it assumes the occupancy theory of agonist action. Pharmacological effect-time profiles are simulated which illustrate (i) the extent to which overt fade may be detectable under different conditions and (ii) the extent to which measured pharmacological effects deviate from those which would be measured in the absence of desensitization. It is shown that the resulting agonist concentration-effect curves may be displaced rightwards from their equilibrium positions and that the agonist dissociation constants estimated from them may be overestimated. Such errors are predicted to occur regardless of whether or not fade is detectable in the effect-time profiles. Estimates of agonist efficacy appears to be unaffected by desensitization. The results of this analysis are discussed with respect to their implications for receptor classification using agonist dissociation constant estimates and for the development of agonist drugs.
D007700:Kinetics; D008433:Mathematics; D008954:Models, Biological; D010600:Pharmacology; D011955:Receptors, Drug / Q000378:metabolism*
D011955:Receptors, Drug