Modification of dose-response curves by effector blockade and uncompetitive antagonism

Kinetic equations were derived for simple models of agonist-antagonist-receptor interaction and used to predict theoretical dose-response curves for the situation where there exists "receptor reserve" and a simple rectangular hyperbolic relation between tissue response and receptor occupancy by agonist, generated by an "effector chain" that links final response to receptor activation. Drug action within this chain, or an "uncompetitive" antagonism exerted by a reversible agonist that combines primarily with the active agonist-receptor complex, may give the appearance of classical noncompetitive or competitive antagonism, depending upon the amount of receptor reserve and upon the rate constants involved in both agonist-receptor and antagonist-receptor interaction. The apparent potency and nature of antagonism by such an uncompetitive antagonist may depend upon the particular agonist against which it is tested. The phenomenon whereby true competitive antagonists reduce the maximal response to a partial agonist can be explained if the partial agonist, in addition to activating receptors, also acts as an uncompetitive antagonist.