title: Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets.
abstract: The phenomenon of functional selectivity, whereby a ligand preferentially directs the information output of a G-protein coupled receptor (GPCR) along (a) particular effector pathway(s) and away from others, has redefined traditional GPCR signaling paradigms to provide a new approach to structure-based drug design. The two principal cannabinoid receptors (CBRs) 1 and 2 belong to the class-A GPCR subfamily and are considered tenable therapeutic targets for several indications. Yet conventional orthosteric ligands (agonists, antagonists/inverse agonists) for these receptors have had very limited clinical utility due to their propensity to incite on-target adverse events. Chemically distinct classes of cannabinergic ligands exhibit signaling bias at CBRs towards individual subsets of signal transduction pathways. In this review, we discuss the known signaling pathways regulated by CBRs and examine the current evidence for functional selectivity at CBRs in response to endogenous and exogenous cannabinergic ligands as biased agonists. We further discuss the receptor and ligand structural features allowing for selective activation of CBR-dependent functional responses. The design and development of biased ligands may offer a pathway to therapeutic success for novel CBR-targeted drugs.
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States; Center for Drug Discovery, Northeastern University, Boston, MA 02115, United States.
authors.forename: Srikrishnan
authors.initials: S
authors.lastname: Mallipeddi
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States; Center for Drug Discovery, Northeastern University, Boston, MA 02115, United States.
authors.forename: David R
authors.initials: DR
authors.lastname: Janero
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States; Center for Drug Discovery, Northeastern University, Boston, MA 02115, United States.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Zvonok
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States; Center for Drug Discovery, Northeastern University, Boston, MA 02115, United States; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, United States. Electronic address: a.makriyannis@neu.edu.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D054314:Drug Inverse Agonism; D006801:Humans; D058990:Molecular Targeted Therapy; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D063386:Cannabinoid Receptor Agonists; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid
keywords: Biased agonism; Drug discovery; Effector pathways; GPCR