In-Target versus Off-Target allosteric modulators of GPCRs

Allosteric modulators represent a new and possibly safer mechanism of action for G protein coupled receptor (GPCR) drugs, whose effect preserve the temporal and local patterns of physiological activity of the endogenous ligand while binding at a different site. We highlight the different molecular mechanisms that could be responsible for this phenotype, distinguishing between the commonly assumed In-Target and potential Off-Target modulators. In-Target modulators are suitable for new chemical entities, while Off-Target may be more suitable for new drug indications.

Section editors:David Sibley – National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, USAC. Anthony Altar – Psychiatric Genomics, Gaithersburg, USATheresa Branchek – Lundbeck Research, Paramus, USA