Antagonists
for the Orphan G‑Protein-Coupled Receptor GPR55 Based on a
Coumarin Scaffold
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Abstract
The
orphan G-protein-coupled receptor GPR55, which is activated by 1-lysophosphatidylinositol
and interacts with cannabinoid (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 an extensive structure–activity relationship
study for GPR55. Selectivity versus the related receptors CB<sub>1</sub>, CB<sub>2</sub>, and GPR18 was assessed. Among the 7-unsubstituted
coumarins selective, competitive GPR55 antagonists were identified,
such as 3-(2-hydroxybenzyl)-5-isopropyl-8-methyl-2<i>H</i>-chromen-2-one (<b>12</b>, PSB-SB-489, IC<sub>50</sub> = 1.77
μM, p<i>A</i><sub>2</sub> = 0.547 μM). Derivatives
with long alkyl chains in position 7 were potent, possibly allosteric
GPR55 antagonists which showed ancillary CB receptor affinity. 7-(1,1-Dimethyloctyl)-5-hydroxy-3-(2-hydroxybenzyl)-2<i>H</i>-chromen-2-one (<b>69</b>, PSB-SB-487, IC<sub>50</sub> = 0.113 μM, <i>K</i><sub>B</sub> = 0.561 μM)
and 7-(1,1-dimethylheptyl)-5-hydroxy-3-(2-hydroxybenzyl)-2<i>H</i>-chromen-2-one (<b>67</b>, PSB-SB-1203, IC<sub>50</sub> = 0.261 μM) were the most potent GPR55 antagonists of the
present series
