Figure 2.

Biased agonism and allosteric modulation of GPCR function. (A) Unbiased orthosteric agonists non-selectively activate G protein and β-arrestin signalling pathways, while biased orthosteric ligands preferentially activate one pathway over the other. Conversely, antagonists competitively inhibit agonist binding and thereby inactivate both G protein and β-arrestin signalling in a balanced fashion. (B) Allosteric modulators bind to sites that are topographically distinct from the orthosteric binding pocket of the receptor. Functionally, positive allosteric modulators enhance (+++) the activity of an orthosteric agonist, while negative allosteric modulators reduce (+) orthosteric activity. Biased allosteric modulators can preferentially enhance (positive; +++) or reduce (negative; +) the activity of a particular pathway (i.e. pathway A) while having no effect (++) and/or antagonizing (+) an alternative pathway (i.e. pathway B) in the presence of an orthosteric agonist. Figure generated with Biorender.com.