A Practical Guide to Approaching Biased Agonism at G Protein Coupled Receptors.

Journal Article (Journal Article)

Biased agonism, the ability of a receptor to differentially activate downstream signaling pathways depending on binding of a "biased" agonist compared to a "balanced" agonist, is a well-established paradigm for G protein-coupled receptor (GPCR) signaling. Biased agonists have the promise to act as smarter drugs by specifically targeting pathogenic or therapeutic signaling pathways while avoiding others that could lead to side effects. A number of biased agonists targeting a wide array of GPCRs have been described, primarily based on their signaling in pharmacological assays. However, with the promise of biased agonists as novel therapeutics, comes the peril of not fully characterizing and understanding the activities of these compounds. Indeed, it is likely that some of the compounds that have been described as biased, may not be if quantitative approaches for bias assessment are used. Moreover, cell specific effects can result in "system bias" that cannot be accounted by current approaches for quantifying ligand bias. Other confounding includes kinetic effects which can alter apparent bias and differential propagation of biological signal that results in different levels of amplification of reporters downstream of the same effector. Moreover, the effects of biased agonists frequently cannot be predicted from their pharmacological profiles, and must be tested in the vivo physiological context. Thus, the development of biased agonists as drugs requires a detailed pharmacological characterization, involving both qualitative and quantitative approaches, and a detailed physiological characterization. With this understanding, we stand on the edge of a new era of smarter drugs that target GPCRs.

Full Text

Duke Authors

Cited Authors

  • Gundry, J; Glenn, R; Alagesan, P; Rajagopal, S

Published Date

  • 2017

Published In

Volume / Issue

  • 11 /

Start / End Page

  • 17 -

PubMed ID

  • 28174517

Pubmed Central ID

  • PMC5258729

International Standard Serial Number (ISSN)

  • 1662-4548

Digital Object Identifier (DOI)

  • 10.3389/fnins.2017.00017


  • eng

Conference Location

  • Switzerland