Cannabidiol (CBD) is one of the major components of Cannabis sativa. This non-psychoactive molecule has shown neuroprotective, antiepileptic, anxiolytic, antipsychotic, and anti-inflammatory properties among others. However, its complex pharmacology it is not yet fully understood.<br/>GPR3 is an orphan receptor that belongs to the Class A family of G-Protein Coupled Receptors. It shares high sequence similarity with GPR6, GPR12, the lysophospholipid receptors S1P1 and LPA1, and the cannabinoid receptors, CB1 and CB2. GPR3 has been shown to be a possible target for the treatment of pathological conditions such as Alzheimer's disease (AD), oocyte maturation or neuropathic pain. Nevertheless, the lack of potent and selective GPR3 modulators is delaying the exploitation of this promising therapeutic target. Interestingly, we have recently discovered that CBD acts as a GPR3 inverse agonist of the G-protein Independent β–arrestin (GprotIndepBarr) signaling pathway, but has no effect on GPR3 G-protein Dependent (GprotDep) signaling. Such GPR3 GprotIndepBarr signaling biased inverse agonists have great therapeutic potential in AD.<br/>In this context, we have developed a GPR3 homology model that may help us to elucidate the structural determinants governing key ligand-receptor interactions. Our GPR3 model is based on the crystallized S1P1 receptor structure. Sequence divergences in transmembrane helixes 1, 4, 6 and 7 have been explored using the Monte Carlo/simulated annealing program, Conformational Memories. The extracellular and intracellular loop geometries were calculated using Modeller v9.1. The GPR3 inactive state model has helped us to elucidate the molecular interactions of CBD with this orphan receptor rationalizing the structural basis of its selective GprotIndepBarr vs. GprotDep signaling. This homology model will enable the design of more potent and selective GprotDep and GprotIndepBarr-biased GPR3 ligands to further understand GPR3’s biological role and its possible relation with the endocannabinoid system.

Non-psychoactive cannabinoid CBD modulates the orphan receptor GPR3

254th National Meeting (2017)

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