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. GPR52 agonists are expected to have potential as a novel class of antipsychotics.We successfully discovered 3-[2-(3-chloro-5-fluorobenzyl)-1-benzothiophen-7-yl]-N-(2-methoxyethyl)benzamide as the first GPR52 agonist. This compound showed potent GPR52 agonistic activity (EC50= 35 nM) and good pharmacokinetic properties. Furthermore, the compound significantly suppressed methanphetamine-induced hyperactivity in mice after oral administration of 3 mg/kg and was devoid of disturbance of motor function in mice.Design and synthesis of the first GPR52 agonist as well as biological evaluation results will be presented.

Discovery of the first potent and orally available agonist of the orphan G protein-coupled receptor 52

247th National Meeting (2014)

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