Introduction: In recent years, it has become clear that individual GPCRs can elicit multiple G-protein-dependent and -independent cellular responses. This has led to the discovery that certain ligands can differentially modulate these responses, a concept known as functional selectivity.
Areas covered: In this review, the authors describe the various manifestations of functional selectivity and its potential implication in drug discovery. The authors provide a historical perspective of the observations and methodologies that led to the evolution of this concept. The authors also describe the proposed molecular mechanisms responsible for the engagement of distinct subsets of signaling repertoire by different ligands. The review offers the reader a synthetic view of how functional selectivity could be used in the design of safer and more effective drugs.
Expert opinion: Our better understanding of the various ways by which compounds modulate GPCR activity has led to a parallel expansion of the terminology used to describe these phenomena. The authors propose a standardization of this nomenclature as an essential step to both simplify and clarify the language used among researchers to facilitate future collaboration and discovery of these important therapeutic targets. Such clarification of the various aspects of functional selectivity, coupled with the development of tools for effective monitoring, will undoubtedly bring this emerging concept into the general paradigm of drug discovery at GPCRs.