Discovery of the First Potent and Orally Available Agonist of the Orphan G-Protein-Coupled Receptor 52

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• 作者：Masaki Setoh ; Naoki Ishii ; Mitsunori Kono ; Yuhei Miyanohana ; Eri Shiraishi ; Toshiya Harasawa ; Hiroyuki Ota ; Tomoyuki Odani ; Naoyuki Kanzaki ; Kazunobu Aoyama ; Teruki Hamada ; Masakuni Kori
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 26, 2014
• 年：2014
• 卷：57
• 期：12
• 页码：5226-5237
• 全文大小：593K
• ISSN：1520-4804

文摘

G-protein-coupled receptor 52 (GPR52) is an orphan Gs-coupled G-protein-coupled receptor. GPR52 inhibits dopamine D₂ receptor signaling and activates dopamine D₁/N-methyl-d-aspartate receptors via intracellular cAMP accumulation, and therefore, GPR52 agonists may have potential as a novel class of antipsychotics. A series of GPR52 agonists with a bicyclic core was designed to fix the conformation of the phenethyl ether moiety of compounds 2a and 2b. 3-[2-(3-Chloro-5-fluorobenzyl)-1-benzothiophen-7-yl]-N-(2-methoxyethyl)benzamide 7m showed potent activity (pEC₅₀ = 7.53 卤 0.08) and good pharmacokinetic properties. Compound 7m significantly suppressed methamphetamine-induced hyperactivity in mice after oral administration of 3 mg/kg without disturbance of motor function.