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.

Oleanane-Type Triterpene Conjugates with 1H-1,2,3-Triazole Possessing of Fungicidal Activity

“…General procedure for the synthesis of compounds 3 and 4 . Slight modifications of the synthesis methods referring to the literature [ 26 , 27 , 28 ] have been made. We use a one-pot method to synthesize 3 and 4 instead of the step-by-step method.…”

Ag‐Catalyzed Remote Dehydrogenative‐coupling of Unactivated C(sp3)−H Alcohols with Quinazolines for the Synthesis of δ‐Hydroxylalkyl Substituted Quinazolines in Aqueous Media

“…Typical procedure for the synthesis of 7 [30] : 2-(5-hydroxypentan-2yl)-4-phenylquinazoline 3 aa (58.5 mg, 0.2 mmol) was dissolved in 2 ml of DCM, and PBr 3 ( 0.2 mmol, 1 eq.) added slowly under vigorous stirring at 0°C.…”

Therapeutic Exploitation of GPR18: Beyond the Cannabinoids?

“…The most potent compound of this series at GPR18 is PSB-18337 (Figure ). This compound exhibits very high potency but low efficacy at GPR55 . Screening a compound library focusing on lipophilic structures, Müller and co-workers identified imidazothiazinone as a GPR18 scaffold using β-arrestin recruitment assays.…”

“…This compound exhibits very high potency but low efficacy at GPR55. 63 Screening a compound library focusing on lipophilic structures, Muller and co-workers 56 identified imidazothiazinone as a GPR18 scaffold using β-arrestin recruitment assays. Further systematic structural modification on this scaffold led to PSB-CB5 56 and PSB-CB27 62 (Figure 5).…”