Antagonists for the Orphan G-Protein-Coupled Receptor GPR55 Based on a Coumarin Scaffold

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• 作者：Viktor Rempel ; Nicole Volz ; Franziska Gl盲ser ; Martin Nieger ; Stefan Br盲se ; Christa E. M眉ller
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4798-4810
• 全文大小：458K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

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鈥檚 disease, neuropathic pain, and cancer. We applied 尾-arrestin assays to identify 3-substituted coumarins as a novel class of antagonists and performed an extensive structure鈥揳ctivity 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 渭M, pA₂ = 0.547 渭M). 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)-2H-chromen-2-one (69, PSB-SB-487, IC₅₀ = 0.113 渭M, K_B = 0.561 渭M) and 7-(1,1-dimethylheptyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (67, PSB-SB-1203, IC₅₀ = 0.261 渭M) were the most potent GPR55 antagonists of the present series.