Biased ligands at G-protein-coupled receptors: promise and progress

Trends Pharmacol Sci. 2014 Jul;35(7):308-16. doi: 10.1016/j.tips.2014.04.007. Epub 2014 May 28.

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.

Keywords: TRV027; TRV130; angiotensin; functional selectivity; opioid; β-arrestin.

Publication types

  • Review

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Animals
  • Drug Design
  • Humans
  • Ligands
  • Oligopeptides / pharmacology
  • Receptor, Angiotensin, Type 1 / metabolism
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Opioid, mu / metabolism
  • Spiro Compounds / pharmacology
  • Thiophenes / pharmacology

Substances

  • ((3-methoxythiophen-2-yl)methyl)((2-(9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl))amine
  • Angiotensin II Type 1 Receptor Blockers
  • Ligands
  • Oligopeptides
  • Receptor, Angiotensin, Type 1
  • Receptors, G-Protein-Coupled
  • Receptors, Opioid, mu
  • Spiro Compounds
  • Thiophenes
  • sarcosine-arginyl-valyl-tyrosyl-isoleucyl-histidyl-prolyl-alanine