What question did this study set out to answer?

This review aims to establish criteria for the systematic evaluation of orphan G protein-coupled receptors and their potential ligands.

May 11, 2026Pharmacological Reviews0 citationsOpen Access

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

SAS P H AlexanderUniversity of Nottingham KBK.A. BennettRedx Pharma (United Kingdom)ABAndrew W. BrownUniversity of Hertfordshire

Key Points

This review aims to establish criteria for the systematic evaluation of orphan G protein-coupled receptors and their potential ligands.
Review of 67 orphan Class A G protein-coupled receptors
Identification of ligands through published research
Assessment of genetic disruption impact on receptor function.
25 orphan Class A GPCRs lack identifiable endogenous agonists; 5 have synthetic ligands.
32 orphan GPCRs are paired with endogenous agonists, mainly lipids and peptides.
10 orphan GPCRs are recommended for further investigation for potential deorphanization.

Abstract

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, Zn 2+ ), GPR65 (protons), GPR68 (protons), GPR132 (9-HODE), GPR183 (7,25-dihydroxycholesterol), MRGPRD (-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.Significance statement (1-2 sentences; 80-word maximum -currently 67)The use of systematic, rational nomenclature for drug targets provides a framework to ensure consistent identification and rapid recognition.Given that G protein-coupled receptors have fundamental physiological roles and are widespread targets of drugs in current clinical use, we hope the target summary and deorphanization criteria provided here will prompt renewed efforts to investigate these orphan receptors as regulators of physiology and opportunities for future therapeutic exploitation.

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