Structure-activity relationships of imidazothiazinones and analogs as antagonists of the cannabinoid-activated orphan G protein-coupled receptor GPR18

Abstract

GPR18 is a cannabinoid-activated orphan G protein-coupled receptor (GPCR) that is selectively expressed on immune cells. Despite its significant potential as a drug target for inflammatory diseases and cancer immunotherapy, only very few GPR18 ligands have been described to date. In the present study we investigated the structure-activity relationships (SARs) of (Z)-2-(3-(4-chlorobenzyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1-b][1,3]thiazin-3(5H)-one (PSB-CB5, 5), the most potent GPR18 antagonist described to date. Analogs were synthesized that exhibit broad modifications of the heterocyclic core and/or variation of substituents at the benzylidene moiety. The compounds were investigated in β-arrestin recruitment assays as inhibitors of human GPR18 activation by tetrahydrocannabinol (THC). Selectivity was assessed versus the cannabinoid receptors (CB₁ and CB₂) and versus GPR55, another orphan GPCR that interacts with cannabinoids. Phenyloxyalkyloxy-substituted benzylidenethiazinones with long alkyl chains (optimal length: hexamethylene) efficiently blocked GPR18 with similarly high potency as lead structure 5. (Z)-2-(3-(6-(4-Chlorophenoxy)hexyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1-b][1,3]thiazin-3(5H)-one (PSB-CB-27, 23) exhibited the best profile: it displayed an IC₅₀ value of 650 nM at GPR18 and showed improved selectivity versus CB receptors as compared to lead structure 5. Importantly, in contrast to 5, which showed only partial inhibition (60%), 23 led to a complete blockade of THC-induced GPR18 activation and is thus a superior tool for target validation. In addition, several compounds, e.g. 18 and 22, were identified as dual GPR18/GPR55 antagonists with similar potency at both targets, and selectivity versus CB receptors.

Keywords: Antagonists; Cannabinoid receptor; GPCR; GPR18; GPR55; Immunotherapy; Inflammation; Orphan receptor; Structure-activity relationships; Synthesis; β-arrestin.