Preference for Glucose over Inositol Headgroup during Lysolipid Activation of G Protein-Coupled Receptor 55

G protein-coupled receptor55 ( GPR55) is highly expressed in brain and peripheral nervous system. Originally deorphanized as a cannabinoid receptor, recently GPR55has been described as a lysophospholipid-responsive receptor, specifically toward lysophosphatidylinositoland lysophosphatidyl-β-d-glucoside (LysoPtdGlc). To characterize lysolipid- GPR55interaction, synthetic access to LysoPtdGlc and selected analogues was established utilizing a phosphorus(III)-based chemical approach. The biological activity of each synthetic lipid was assessed using a GPR55-dependent chemotropismassay in primary sensory neurons. Combined with molecular dynamics simulations the potential ligand entry port and binding pocket specifics are discussed. These results highlight the preference for gluco- over inositol- and galacto-configured headgroups.