International Union of Basic and Clinical Pharmacology xxx: Applying an objective evaluation to the status of Class A orphan G protein-coupled receptors

In this review, we, on behalf of the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), describe criteria for assessing the evidence for pairing receptors and endogenous/physiological ligands for formal receptor deorphanization. This process is illustrated through consideration of the Class A G protein-coupled receptors (GPCR) not yet formally paired with an endogenous/physiological ligand by NC-IUPHAR. Of the 67 orphan Class A GPCR considered, twenty-five Class A GPCRs have no identified endogenous agonists, although five (GPR21, GPR27, GPR52, GPR85 and GPR88) have synthetic ligands that have the potential to be used as tools for uncovering physiological roles and further pharmacological properties of these receptors. Surprisingly, six orphan GPCRs (GPR135, GPR152, GPR153, MRGPRF, MRGPRG and MRGPRX3) have no clear pharmacology or phenotype reported following genetic disruption. Thirty-two orphan GPCRs have been paired with at least one endogenous agonist (mainly lipids and their derivatives, peptides and other metabolites) but further characterization is required from the scientific community to validate these results. We identify 10 orphan Class A orphan GPCRs for which there are plausible grounds for considering deorphanization: GPR4 (protons), GPR15 (GPR15L), GPR31 (12S-HETE), GPR39 (zinc divalent ions, Zn2+), GPR65 (protons), GPR68 (protons), GPR132 (9-HODE), GPR183 (7α,25-dihydroxycholesterol), MRGPRD (β-alanine) and MRGPRX1 (bovine adrenal medulla peptide, BAM-8-22). The issue of nomenclature of these 10 GPCRs will be considered by further subcommittees of NC-IUPHAR. We hope this review will prompt further investigations of these members of the currently most widely clinically exploited protein superfamily.