Introduction to Receptor Theory

Summary

This chapter provides a synopsis of the development of the receptor concept to explain differential tissue distribution and ultimate specificity of drug action. A relationship between available drug concentration and the proportion of receptors occupied was quickly advanced which implied that drug-receptor interactions obey mass action principles, in a manner analogous to enzyme-substrate interactions. However, Clark’s postulate that the extent of receptor occupancy correlated directly with the extent of elicited response did not explain the majority of experimental findings. To explain the frequent observation that a maximal response could be elicited by occupying only a small fraction of the total receptor population, Stephenson postulated that drugs possess varying efficacies, such that a maximal response can be evoked by occupying differing fractions of the receptor population. Black and Leff have offered a quantitative description of occupancy/response relationships that permits calculation of a transducer ratio for comparison of entire dose-response curves in different tissues or following various experimental manipulations, bringing the quantification of practical descriptors to the nonlinear occupancy-response relationships first introduced by Stephenson. Allosteric models were proposed to account for anomalous antagonisms as well as nonhyperbolic dose-response relationships alluded to earlier. However, multi-state, rather than two-state, models are necessary to describe the varying orders of potencies of a single agonist at a single receptor in evoking different signal outputs.

Distinguishing among the many molecular models that explain how receptor occupancy is linked to biological response ultimately requires purification of the receptor and reconstitution with its purified “effector system,” be it ion translocation or modulation of enzymatic activities. Rigorous characterization of the receptor-response system in the intact target cell is a crucial prerequisite for ultimately understanding the molecular basis for the physiological response observed in vivo, as it is only to the extent that the purified and reconstituted assembly mimics the native receptor-response system that the in vitro system can provide unequivocal insights into receptor mechanisms. Chapter 2 summarizes available methods for determining receptor specificity, the affinity of the putative receptor for its specific agonist, partial agonist, and antagonist agents based on measurements of receptor-mediated response.