G protein coupled receptors (GPCRs) comprise a large superfamily of receptors characterized by a seven transmembrane domain structure and an ability to activate intracellular transducer G proteins. Over 800 GPCRs in five main families have been identified in eukaryotes on the basis of genomic sequence analysis ^1-2. These receptors can be activated by hormones, neurotransmitters, odorants, light, or pheromones. GPCRs mediate the signaling of extracellular stimuli to intracellular responses via activation of heterotrimeric G proteins and their subsequent interaction with effector proteins. GPCRs have been implicated in a number of physiological functions including development of anxiety, behavior, homeostasis, cognition, appetite, and drug addiction ³. The GPCR family contains a diverse group of cell-surface mediators of signal transduction, its size exceeding other cell-surface protein receptors including the tyrosine kinase receptors, guanylyl cyclase receptors and ligand-gated ion channels ⁴.

The murine homolog of GPR18 was first isolated in 1996 ⁵. A potential agonist for this orphan receptor was proposed only in 2006 when N-arachidonylglycine (NAGly) was shown to increase calcium concentration and inhibit forskolin induced cAMP production in CHO cells in a pertussis sensitive manner ⁶.

GPR18 shares low sequence homology with the cannabinoid receptors CB₁R and CB₂R (~13% and 8%) and moderate identity with the putative cannabinoid receptor GPR55 (21%). Nonetheless, it has been related to the endocannabinoid system since a range of endogenous, phytogenic and synthetic cannabinoids have shown to modulate GPR18 ⁷.

GPR18 was shown to be constitutively active in melanomas, acting as an apoptosis inhibitor ⁸, while playing a reverse role in macrophage apoptosis, that is, signaling for cell death⁹. Both of these roles were mediated via Gαi pathways. Work on alternate cannabinoid compounds as potential agonist showed differential activation of Gαq / Gαi signaling suggesting biased agonism in pathway selection¹⁰.