The orphan G protein-coupled receptor GPR55, which is activated by 1 lysophosphatidylinositol and interacts withcannabinoid (CB) receptor ligands, has been proposed as a new potential drug target for the treatment of diabetes, Parkinson’s disease, neuropathic pain, and cancer. We applied β-arrestin assays to identify 3-substituted coumarins as a novel class of antagonists, and performed the first extensive structure-activity relationship study for GPR55. Selectivity versus the related receptors CB₁, CB₂ and GPR18 was assessed. Among the 7-unsubstituted coumarins selective, competitive GPR55 antagonists were identified, such as 3-(2-hydroxybenzyl)-5-isopropyl-8-methyl-2H-chromen-2-one (12, PSB-SB-489, IC₅₀ 1.77 µM, pA₂ 0.547 µM). Derivatives with long alkyl chains in position 7 were potent, allosteric GPR55 antagonists which showed ancillary CB receptor affinity. 7-(1,1-Dimethyloctyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (69, PSB-SB-487, IC₅₀ 0.113 µM, K_B 0.561 µM) and 7-(1,1-dimethylheptyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (67, PSB-SB-1203, IC₅₀ 0.261 µM) were the most potent GPR55 antagonists of the present series.

PMID:

 

23679955

 

[PubMed – as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/23679955