“It is now clear that, in contrast to traditional descriptions of G protein-coupled receptor signaling, agonists can activate or inhibit characteristic patterns of downstream effector pathways depending on their structures and the conformational changes induced in the receptor. This is referred to as functional selectivity (also known as agonist-directed trafficking, ligand-induced differential signaling, or biased agonism). It is important because even small structural differences can result in significant variations in overall agonist effects (wanted and unwanted) depending on which postreceptor signaling systems are engaged by each agonist/receptor pairing. In addition to the canonical signaling pathways mediated by Gi/o proteins, CB1 and CB2 receptor agonists can have effects via differential activation not only of Gi subtypes but also of Gs and Gq/11 proteins. For example, the classical cannabinoid HU-210 produces maximal activation of both Gi and Go proteins, while the endocannabinoid anandamide and aminoalkylindole WIN 55,212 both produce maximal activation of Gi, but submaximal activation of Go. Cannabinoid agonists can also signal differentially via β-arrestins coupled to mitogen-activated protein kinases, subsequently promoting varying degrees of receptor internalization and agonist desensitization. A recent extensive characterization of the molecular pharmacology of CB2 agonists (Soethoudt et al., 2017) identified marked differences (bias) in the ability of certain agonists to activate distinct signaling pathways (cAMP accumulation, ERK phosphorylation, GIRK activation, GTPγS binding, and β-arrestin recruitment) and to cause off-target effects, exemplifying the need to evaluate functional selectivity in agonist drug development.”
https://www.ncbi.nlm.nih.gov/pubmed/28826535
http://www.sciencedirect.com/science/article/pii/S1054358917300285?via%3Dihub
