Discovery of Tricyclic Xanthines as Agonists of the Cannabinoid-Activated Orphan G-Protein-Coupled Receptor GPR18,ACS Medicinal Chemistry Letters

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Discovery of Tricyclic Xanthines as Agonists of the Cannabinoid-Activated Orphan G-Protein-Coupled Receptor GPR18
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-06-17 , DOI: 10.1021/acsmedchemlett.0c00208
Clara T Schoeder _{1,

2} , Andhika B Mahardhika _{1,

2} , Anna Drabczyńska ₃ , Katarzyna Kieć-Kononowicz ₃ , Christa E Müller ₁

Affiliation

GPR18 is a rhodopsin-like orphan G-protein-coupled receptor (GPCR) that is activated by the natural cannabinoid (CB) Δ⁹-tetrahydrocannabinol (THC). It is highly expressed in immune cells and represents a promising new drug target. However, THC is much more potent in activating CB receptors than GPR18, and several other proposed lipidic agonists for GPR18 have not been independently confirmed. Herein we describe the first non-lipid-like agonists for GPR18 based on a tricyclic xanthine-derived scaffold, along with initial structure–activity relationships. PSB-KD107 (5) and PSB-KD477 (16) displayed significantly higher potency and efficacy than THC, determined in a GPR18-dependent β-arrestin recruitment assay, and were found to be selective versus the CB-sensitive receptors CB₁, CB₂, and GPR55. Structure–activity relationships were steep, and indole substitution was crucial for biological activity. These first selective agonists, which are structurally distinct from the lipidic agonist(s), will allow target validation studies and may eventually contribute to the deorphanization of GPR18.

中文翻译：

发现三环黄嘌呤作为大麻素激活的孤儿 G 蛋白偶联受体 GPR18 的激动剂

GPR18 是一种视紫质样孤儿 G 蛋白偶联受体 (GPCR)，由天然大麻素 (CB) Δ ⁹ -四氢大麻酚 (THC)激活。它在免疫细胞中高度表达，代表了一个有前途的新药物靶点。然而，THC 在激活 CB 受体方面比 GPR18 更有效，并且其他几种提议的 GPR18 脂质激动剂尚未得到独立证实。在此，我们描述了第一个基于三环黄嘌呤衍生支架的 GPR18 非脂质样激动剂，以及初始结构-活性关系。PSB-KD107 ( 5 ) 和 PSB-KD477 ( 16) 显示出比 THC 显着更高的效力和功效，在 GPR18 依赖性 β-抑制蛋白募集试验中确定，并且被发现对 CB 敏感受体 CB ₁、CB ₂和 GPR55 具有选择性。构效关系陡峭，吲哚取代对生物活性至关重要。这些第一个选择性激动剂在结构上与脂质激动剂不同，将允许进行目标验证研究，并可能最终有助于 GPR18 的脱孤。

更新日期：2020-06-17

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