Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery

Trends Pharmacol Sci. 2021 Apr;42(4):283-299. doi: 10.1016/ Epub 2021 Feb 10.


G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in the genome and the most successful family of targets of FDA-approved drugs. New frontiers in GPCR drug discovery remain, however, as achieving receptor subtype selectivity and controlling off- and on-target side effects are not always possible with classic agonist and antagonist ligands. These challenges may be overcome by focusing development efforts on allosteric ligands that confer signaling bias. Biased allosteric modulators (BAMs) are an emerging class of GPCR ligands that engage less well-conserved regulatory motifs outside the orthosteric pocket and exert pathway-specific effects on receptor signaling. The unique ways that BAMs texturize receptor signaling present opportunities to fine-tune physiology and develop safer, more selective therapeutics. Here, we provide a conceptual framework for understanding the pharmacology of BAMs, explore their therapeutic potential, and discuss strategies for their discovery.

Keywords: G protein-coupled receptor (GPCR); allosteric modulation; drug development; functional selectivity; signaling bias; β-arrestin.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Allosteric Regulation
  • Drug Discovery*
  • Ligands
  • Receptors, G-Protein-Coupled*
  • Signal Transduction


  • Ligands
  • Receptors, G-Protein-Coupled