Theories of drug action, 100 years of progress: From occupation to biased signaling contributions

Abstract

A.J. Clark applied the law of mass action to explain how drugs work, a formulation known as the occupation theory. This hypothesis advanced that drugs occupy receptors through the formation of a [drug-receptor] complex intimately linked to the generation of a pharmacologic response. Full agonists were distinguished from antagonists based on the nature of the complex formed and concentration-response curves. Stephenson introduced the notion of drug efficacy and intrinsic activity to modify Clark’s proposal, explaining why antagonists, which occupy receptors, do not elicit a direct receptor-mediated response. According to this modification, partial agonists do not achieve full efficacy due to low intrinsic activity based on dose-response curves, while antagonists dramatically lack all intrinsic activity. Detailed structural biology findings of GPCRs provided new insights into possible conformational changes through the multiple forms of [drug-receptor] complexes, which ultimately cause clinical responses. Moreover, the recognition that several β-arrestins produce GPCRs' intracellular signaling through the activation of various protein kinases accounts for the novel idea that drugs that interact preferentially through this intracellular pathway, such as receptor antagonists, also elicit cellular responses. The evolution of these ideas proposed that drugs interact with the multiple receptor conformations, eliciting interactions that consequently elicits varying states of receptor activity, followed by ensuing intracellular responses. This new proposal changed the nomenclature from full agonists to selective G protein ligands and antagonists as preferential β-arrestins ligands. Agonists and antagonists are all now referred to as receptor ligands, independent of the nature of the [drug-receptor] complex formed.