GPR18 is an orphan G-protein coupled receptor (GPCR) mainly expressed in both central and lymphoid tissues that participates in a myriad of physiological functions such as intraocular pressure, cellular migration, apoptosis, nociception or immunomodulation. Hence, this receptor constitutes a very interesting therapeutic target. While numerous cannabinoid ligands have been reported to stimulate GPR18 – including NAGly, Abn-CBD and Δ9-THC – few synthetic compounds have been designed to modulate this GPCR.
Based on an in silico model of GPR18, a series of new compounds with a cannabinoid-like scaffold have been designed and synthesized. Pharmacological evaluation has shown that several of these new compounds were able to activate GPR18 in calcium mobilization studies, whereas others strongly antagonized the effect of NAGly in these assays.
