International Union of Basic and Clinical Pharmacology. CXXII. Applying an objective evaluation to the status of class A orphan G protein-coupled receptors. - 2026
International Union of Basic and Clinical Pharmacology. CXXII. Applying an objective evaluation to the status of class A orphan G protein-coupled receptors.
Alexander, Stephen P H; Bennett, Kirstie A; Brown, Andrew Jet al.
2026 • In Pharmacological Reviews, 78 (4), p. 100141
[en] In this review, we, on behalf of the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology, describe criteria for assessing the evidence for pairing receptors with endogenous/physiological ligands for formal receptor deorphanization. This process is illustrated through consideration of the class A G protein-coupled receptors (GPCRs) not yet formally paired with an endogenous/physiological ligand by the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology. Of the 67 orphan class A GPCRs considered, 25 class A GPCRs have no identified endogenous agonists, although 5 (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, 6 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 1 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 GPCRs for which there are plausible grounds for considering deorphanization: GPR4 (protons), GPR15 (GPR15L), GPR31 (12S-hydroxyeicosatetraenoic acid), GPR39 (zinc divalent ions, Zn2+), GPR65 (protons), GPR68 (protons), GPR132 (9-hydroxyoctadecadienoic acid), GPR183 (7α,25-dihydroxycholesterol), MRGPRD (β-alanine), and MRGPRX1 (bovine adrenal medulla peptide 8-22). The issue of nomenclature for these 10 GPCRs will be considered by further subcommittees of the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology. We hope this review will prompt further investigations into these members of the currently most widely clinically exploited protein superfamily. SIGNIFICANCE STATEMENT: 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 as opportunities for future therapeutic exploitation.
Alexander, Stephen P H ; Division of Physiology, Pharmacology and Neuroscience, Life Sciences, University of Nottingham Medical School, Nottingham, United Kingdom. Electronic address: steve.alexander@nottingham.ac.uk
Bennett, Kirstie A; Nxera Pharma UK Ltd, Cambridge, United Kingdom
Brown, Andrew J ; Ikherma Consulting Ltd, Hertfordshire, United Kingdom
Glass, Michelle; School of Pharmacy and Pharmacology, University of Otago, Otago, New Zealand
Gloriam, David E ; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
Hanson, Julien ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Insel, Paul A; Departments of Pharmacology and Medicine, University of California, San Diego, La Jolla, California
Kelly, Eamonn; School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
Langmead, Christopher J ; Drug Discovery Biology and Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
Martemyanov, Kirill A; Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, Florida
Neubig, Rick R; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan and Nicholas V. Perricone, MD, Division of Dermatology, Department of Medicine, College of Human Medicine, East Lansing, Michigan
Offermanns, Stefan ; Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim Germany and Center for Molecular Medicine, Goethe-University Frankfurt, Frankfurt am Main, Germany
Rosenkilde, Mette M ; Department of Biomedical Sciences, Lab for Molecular Pharmacology, University of Copenhagen, Copenhagen, Denmark
Schulte, Gunnar ; Department Physiology and Pharmacology, Section of Receptor Biology and Signaling, Karolinska Institutet, Stockholm Sweden
Smith, Nicola J ; Orphan Receptor Laboratory, Department of Pharmacology, School of Biomedical Sciences, Faculty of Medicine & Health, UNSW Sydney, Sydney, Australia
Wu, Huixian ; Medicine Design, Pfizer Research and Development, Pfizer Inc, Groton, Connecticut
Faccenda, Elena ; Institute for Neuroscience and Cardiovascular Research, College of Medicine & Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom
Harding, Simon D; Institute for Neuroscience and Cardiovascular Research, College of Medicine & Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom
Davenport, Anthony P ; Experimental Medicine and Immunotherapeutics, Department of Medicine, University of Cambridge, Level 6, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom
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