Development of Chromen-4-one Derivatives as (Ant)agonists for the Lipid-Activated G Protein-Coupled Receptor GPR55 with Tunable Efficacy

Abstract

The lipid-activated G protein-coupled receptor (GPCR) GPR55 has been proposed as a drug target for the treatment of chronic diseases including inflammation, neurodegeneration, neuropathic pain, metabolic diseases, and cancer. A series of chromen-4-one-2-carboxylic acid derivatives was synthesized with the aim to obtain potent and selective ligands for GPR55 by (i) attachment of a variety of substituted 8-benzamido residues, (ii) substitution in position 6 by halogen atoms, and (iii) thioation of the 4-oxo function. The compounds were investigated in β-arrestin recruitment assays using enzyme complementation. Depending on the substitution pattern, a spectrum of efficacies was obtained ranging from (partial) agonists to antagonists. 6-Chloro-8-(3-((5-cyclohexylpentyl)oxy)benzamido)-4-oxo-4H-chromene-2-carboxylic acid (74, PSB-18251) displayed the highest efficacy of the series combined with high potency (EC50 0.196 μM). 6-Chloro-8-(3-(heptyloxy)benzamido)-4-oxo-4H-chromene-2-carboxylic acid (76, PSB-18337) exhibited higher potency (EC50 0.0400 μM) but lower efficacy (39%). Several GPR55 antagonists were discovered including 8-(3-(cyclohexylmethoxy)benzamido)-4-oxo-4H-chromene-2-carboxylic acid (57, PSB-18263) (IC50 8.23 μM) and 4-oxo-8-(3-phenethoxybenzamido)-4H-chromene-2-carboxylic acid (65, PSB-18270) (IC50 3.96 μM). These potent GPR55 agonists and antagonists showed high selectivity versus the related GPCRs GPR18 and GPR35 tested in the same assay system, while 8-(4-(4-cyclohexylbutoxy)benzamido)-6-fluoro-4-oxo-4H-chromene-2-carboxylic acid (84, PSB-18177) represents a dual GPR35/GPR55 antagonist (IC50 GPR55: 3.26 μM, GPR35: 2.57 μM). Binding studies of selected compounds at CB1 and CB2 receptors indicated GPR55 selectivity also versus CB receptors. The newly developed GPR55 (partial) agonists and antagonists will be useful tools for evaluating the suitability of GPR55 as a drug target.