GPR18 is a G-protein-coupled receptor that belongs to the orphan class A family. Even though it shares low sequence homology with the cannabinoid receptors CB1R and CB2R, a growing body of research suggests its relationship with the endocannabinoid system, not only because it is able to recognize cannabinoid ligands but also because of its expression and ability to heteromerize with CBRs. In this review, we aim to analyze the biological relevance, reported modulators, and structural features of GPR18. In order to guide future drug design in this field, highlights from molecular modeling of GPR18 will be provided.

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Cannabinoids have shown to exert their therapeutic actions through a variety of targets. These include not only the canonical cannabinoid receptors CB1R and CB2R but also related orphan G protein-coupled receptors (GPCRs), ligand-gated ion channels, transient receptor potential (TRP) channels, metabolic enzymes, and nuclear receptors. In this review, we aim to summarize reported compounds exhibiting their therapeutic effects upon the modulation of CB1R and/or CB2R and the nuclear peroxisome proliferator-activated receptors (PPARs). Concomitant actions at CBRs and PPARα or PPARγ subtypes have shown to mediate antiobesity, analgesic, antitumoral, or neuroprotective properties of a variety of phytogenic, endogenous, and synthetic cannabinoids. The relevance of this multitargeting mechanism of action has been analyzed in the context of diverse pathologies. Synergistic effects triggered by combinatorial treatment with ligands that modulate the aforementioned targets have also been considered. This literature overview provides structural and pharmacological insights for the further development of dual cannabinoids for specific disorders.

Synthesis. A new family of GPR18 ligands were synthesized following procedure exemplified in Scheme 1. Calcium imaging. Intracellular calcium measurements were performed in hGPR18-CHO-K1 cells, following a procedure previously described by us 1. Docking. Global minimum energy conformers of each ligand were carried out with ab initio Hartree-Fock 6-31G* calculations with Spartan (Wave Function, Inc., Irvine CA) and manually docked into the receptor model previously published 2. METHODS GPR18 is an orphan GPCR highly expressed in lymphoid tissues and the central nervous system that regulates cellular migration, proliferation, nociociception, and immunomodulation. The endocannabinoid derivative N-Arachidonoylglycine (NAGly) has been proposed as the putative endogenous ligand. Several other cannabinoids also interact with GPR18, such as Abn-CBD and Δ 9-THC. However, very few potent synthetic GPR18 ligands have been described so far. A new family of compounds based on the cannabidiol scaffold were designed to target GPR18. Calcium mobilization imaging studies 1 and docking studies in a in silico model 2 were used to evaluate the activity of compounds and their mechanism of action, respectively. Here, two of the best compounds are exemplified: S5, a GPR18 agonist, and S4, a GPR18 antagonist.