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

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/<i>N</i>-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 <b>2a</b> and <b>2b</b>. 3-[2-(3-Chloro-5-fluorobenzyl)-1-benzothiophen-7-yl]-<i>N</i>-(2-methoxyethyl)­benzamide <b>7m</b> showed potent activity (pEC₅₀ = 7.53 ± 0.08) and good pharmacokinetic properties. Compound <b>7m</b> significantly suppressed methamphetamine-induced hyperactivity in mice after oral administration of 3 mg/kg without disturbance of motor function