Molecular Pharmacology Fast Forward. Published on May 24, 2011 as doi: 10.1124/mol. 111.072801

Abstract Seven transmembrane receptors (7TMRs), commonly referred to as G protein-coupled receptors (GPCRs), form a large part of the druggable genome. 7TMRs can signal through parallel pathways simultaneously, such as through heterotrimeric G proteins from different families, or, as more recently appreciated, through the multifunctional adapters, β-arrestins. Biased agonists, which signal with different efficacies to a receptor’s multiple downstream pathways, are useful tools for deconvoluting this signaling complexity. These compounds may also be of therapeutic utility as they have distinct functional and therapeutic profiles from ‘balanced agonists’. Although some methods have been proposed to identify biased ligands, no comparison of these methods applied to the same set of data has been performed. Therefore, at this time there are no generally accepted methods to quantify the relative bias of different ligands, making studies of biased signaling difficult. Here, we use complementary computational approaches for the quantification of ligand bias and demonstrate their application to two well-known drug targets, the β2 adrenergic (β2AR) and angiotensin II type 1A (AT1AR) receptors. The strategy outlined here allows a quantification of ligand bias and the identification of weakly biased compounds. This general methodology should aid in deciphering complex signaling pathways and may also be useful for the development of novel biased therapeutic ligands as drugs.