THE CUBIC TERNARY COMPLEX RECEPTOR-OCCUPANCY MODEL .2. UNDERSTANDING APPARENT AFFINITY

In part I of this series of papers, we described the cubic ternary com plex (CTC) model. In part II, we examine the pharmacological notion of apparent ligand affinity in the light of this model. The high degree of symmetry that characterizes the CTC model makes it possible to use simple geometrical devices to visualize chemical transitions. This geo metric point of view provides a motivation for the development of a bi ological interpretation for apparent affinity. Using this geometrical point of view, an analytical expression for apparent ligand affinity i s derived that can be applied to any receptor-occupancy model. When un bound receptors are distributed among a number of states, apparent aff inity is a composite measure, a weighted average of the affinities tha t a ligand has for each of the receptor states. In general, apparent a ffinity can be interpreted as the mathematical expectation of the simp le affinities of members of a native receptor ensemble. The ''expectat ion'' method of computing apparent affinity is algebraically equivalen t to an even simpler computational method, here called the ''diagonali zation'' method. The use of each method is demonstrated. The CTC model corroborates what other models and some experimental work have previo usly suggested. Affinity, as it is calculated experimentally for G-pro tein-coupled receptors, is not purely a receptor property but is a fun ction both of the receptor and of the suite of transitional proteins w ith which the receptor interacts. (C) 1996 Academic Press Limited