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Published on: June 28, 2019
Targeting GPR18: Structural modelling, ligand discovery, and therapeutic potential in neuroinflammatory disorders
Daniel Tortolani1, Lucia Scipioni2, Francesca Ciaramellano2
1Department of Pharmacy-Pharmaceutical Sciences, University of Bari "Aldo Moro", 70125 Bari, Italy; European Center for Brain Research/Fondazione Santa Lucia IRCCS, 00143 Rome, Italy.
Biochemical Pharmacology
|May 11, 2026
Summary
G protein-coupled receptor 18 (GPR18) is now recognized as a key part of the extended endocannabinoid system. This review highlights GPR18
Area of Science:
- Pharmacology
- Neuroscience
- Molecular Biology
Background:
- G protein-coupled receptor 18 (GPR18) was initially considered an orphan receptor with undefined roles.
- Emerging evidence suggests GPR18 is a significant component of the extended endocannabinoid system (ECS).
- GPR18 shows greater similarity to cannabinoid receptor 2 (CB2R) than cannabinoid receptor 1 (CB1R) in signaling, distribution, and pharmacology.
Purpose of the Study:
- To provide an updated overview of GPR18 biology using diverse analytical methods.
- To refine understanding of GPR18 structure, ligand-binding, and constitutive activity.
- To explore GPR18's role in neuroinflammation and its therapeutic potential.
Main Methods:
- Comparative analysis of AlphaFold-predicted structures versus homology models.
- Literature mining and analysis of Human Protein Atlas transcriptomic/proteomic data.
- In silico chemoinformatic approaches, including PLATO-based target fishing.
Main Results:
- GPR18 expression is concentrated in immune, vascular, and neuroglial tissues.
- GPR18 is implicated in neuroinflammation, potentially mediating resolution pathways and neuroprotection.
- Functional interplay between GPR18 and CB2R is proposed in neuroinflammatory contexts.
- Chemoinformatics identified broader networks and strategies for dual GPR18/CB2R modulators.
Conclusions:
- GPR18 is a characterized component of the endocannabinoid interactome, not an orphan receptor.
- GPR18 shows promise as a therapeutic target for neuroinflammatory and neurodegenerative diseases.
- Further validation is required to confirm GPR18's clinical therapeutic potential.
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