IUPHAR Committee Identifies 10 Class A Orphan GPCRs with Plausible Endogenous Ligands for Deorphanization
Background
Orphan G protein-coupled receptors (GPCRs) represent a significant challenge and opportunity in drug discovery, as their endogenous ligands and physiological functions remain unknown. Despite being the largest family of therapeutic targets, the lack of identified activators or inhibitors for these receptors hinders research into their biological roles and the development of new drugs. Class A GPCRs, in particular, constitute the most widely clinically exploited protein superfamily, making their deorphanization crucial for uncovering novel pharmacological opportunities and advancing fundamental biological understanding. This review addresses this gap by establishing objective criteria for evaluating deorphanization evidence.
Study Design
The Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (IUPHAR) developed and applied objective criteria for assessing the evidence required to formally pair receptors with their endogenous/physiological ligands, a process known as deorphanization. This systematic evaluation focused on 67 class A G protein-coupled receptors (GPCRs) that had not yet been formally deorphanized by the committee. The review meticulously analyzed existing pharmacological data, including ligand binding and functional assays, as well as reported phenotypes following genetic disruption, to determine the strength of evidence for each orphan GPCR's potential ligand identification and physiological role.
Results
Of the 67 class A orphan GPCRs considered, 25 were found to have no identified endogenous agonists, although 5 (GPR21, GPR27, GPR52, GPR85, and GPR88) possess synthetic ligands that could serve as tools for further research. Surprisingly, 6 orphan GPCRs (GPR135, GPR152, GPR153, MRGPRF, MRGPRG, and MRGPRX3) showed no clear pharmacology or reported phenotype following genetic disruption, highlighting a significant knowledge gap. While 32 orphan GPCRs had been tentatively paired with at least 1 endogenous agonist (predominantly lipids and their derivatives, peptides, and other metabolites), these pairings require further rigorous characterization and validation from the scientific community.
The review identified 10 class A orphan 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), andMRGPRX1(bovine adrenal medulla peptide 8-22). Nomenclature for these 10 GPCRs will be further deliberated by subsequent IUPHAR subcommittees.
Key Findings
- 67 class A orphan GPCRs were systematically evaluated for deorphanization evidence.
- 25 orphan GPCRs lack identified endogenous agonists, though 5 have synthetic tool compounds.
- 32 orphan GPCRs have proposed agonists but require further scientific validation.
- 10 class A orphan GPCRs were identified with plausible endogenous ligands for deorphanization.
- Proposed ligands include GPR15L, protons, Zn2+, β-alanine, and bovine adrenal medulla peptide 8-22.
Why It Matters
Identifying plausible ligands for orphan GPCRs unlocks critical new avenues for drug discovery and therapeutic development. This systematic evaluation provides a much-needed roadmap for researchers, directing efforts towards the most promising targets among the vast landscape of uncharacterized receptors. For peptide users and biohackers, the deorphanization of receptors like GPR15 with GPR15L or MRGPRX1 with bovine adrenal medulla peptide 8-22 could lead to the discovery of novel peptide-based interventions. Understanding the physiological roles of these newly paired GPCRs could reveal unexpected pathways for modulating metabolism, inflammation, or neurological function, potentially informing future protocols or combinations. The work highlights the critical need for further experimental validation to translate these findings into usable clinical or research tools, moving us closer to targeted therapies.
gpcr
orphan-receptor
deorphanization
pharmacology
drug-discovery
ligand-identification