Affiliation:
1. Department of Medicine and Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425; and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401
Abstract
Abstract
Conventional orthosteric drug development programs targeting G protein-coupled receptors (GPCRs) have focused on the concepts of agonism and antagonism, in which receptor structure determines the nature of the downstream signal and ligand efficacy determines its intensity. Over the past decade, the emerging paradigms of “pluridimensional efficacy” and “functional selectivity” have revealed that GPCR signaling is not monolithic, and that ligand structure can “bias” signal output by stabilizing active receptor states in different proportions than the native ligand. Biased ligands are novel pharmacologic entities that possess the unique ability to qualitatively change GPCR signaling, in effect creating “new receptors” with distinct efficacy profiles driven by ligand structure. The promise of biased agonism lies in this ability to engender “mixed” effects not attainable using conventional agonists or antagonists, promoting therapeutically beneficial signals while antagonizing deleterious ones. Indeed, arrestin pathway-selective agonists for the type 1 parathyroid hormone and angiotensin AT1 receptors, and G protein pathway-selective agonists for the GPR109A nicotinic acid and μ-opioid receptors, have demonstrated unique, and potentially therapeutic, efficacy in cell-based assays and preclinical animal models. Conversely, activating GPCRs in “unnatural” ways may lead to downstream biological consequences that cannot be predicted from prior knowledge of the actions of the native ligand, especially in the case of ligands that selectively activate as-yet poorly characterized G protein-independent signaling networks mediated via arrestins. Although much needs to be done to realize the clinical potential of functional selectivity, biased GPCR ligands nonetheless appear to be important new additions to the pharmacologic toolbox.
Subject
Endocrinology,Molecular Biology,General Medicine
Reference168 articles.
1. The state of GPCR research in 2004;Ellis;Nat Rev Drug Discov,2004
2. On the application of “a plausible model” of allosteric proteins to the receptor for acetylcholine;Karlin;J Theor Biol,1967
3. On the analysis of pharmacological experiments in terms of an allosteric receptor model;Thron;Mol Pharmacol,1973
4. Operational models of pharmacological agonist;Black;Proc R Soc Lond [Biol],1983
5. An operational model of pharmacological agonism: The effect of E/[A] curve shape on agonist dissociation constant estimation;Black;Br J Pharmacol,1985
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