title: Biased ligands at G-protein-coupled receptors: promise and progress.
abstract: Drug discovery targeting G protein-coupled receptors (GPCRs) is no longer limited to seeking agonists or antagonists to stimulate or block cellular responses associated with a particular receptor. GPCRs are now known to support a diversity of pharmacological profiles, a concept broadly referred to as functional selectivity. In particular, the concept of ligand bias, whereby a ligand stabilizes subsets of receptor conformations to engender novel pharmacological profiles, has recently gained increasing prominence. This review discusses how biased ligands may deliver safer, better tolerated, and more efficacious drugs, and highlights several biased ligands that are in clinical development. Biased ligands targeting the angiotensin II type 1 receptor and the μ opioid receptor illustrate the translation of the biased ligand concept from basic biology to clinical drug development.
authors.affiliation: Trevena Inc., 1018 West 8th Avenue, Suite A, King of Prussia, PA 19406, USA. Electronic address: jviolin@trevenainc.com.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Violin
authors.affiliation: Trevena Inc., 1018 West 8th Avenue, Suite A, King of Prussia, PA 19406, USA.
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Crombie
authors.affiliation: Trevena Inc., 1018 West 8th Avenue, Suite A, King of Prussia, PA 19406, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Soergel
authors.affiliation: Trevena Inc., 1018 West 8th Avenue, Suite A, King of Prussia, PA 19406, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lark
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D015195:Drug Design; D006801:Humans; D008024:Ligands; D009842:Oligopeptides / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: C586842:((3-methoxythiophen-2-yl)methyl)((2-(9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl))amine; D047228:Angiotensin II Type 1 Receptor Blockers; D008024:Ligands; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds; D013876:Thiophenes; C555534:Sar-Arg-Val-Tyr-Ile-His-Pro-Ala-OH
keywords: TRV027; TRV130; angiotensin; functional selectivity; opioid; β-arrestin