title: Discovery of the first potent and orally available agonist of the orphan G-protein-coupled receptor 52.
abstract: 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 ± 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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd. , 26-1, Muraoka-higashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Setoh
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishii
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Kono
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Miyanohana
authors.forename: Eri
authors.initials: E
authors.lastname: Shiraishi
authors.forename: Toshiya
authors.initials: T
authors.lastname: Harasawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ota
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Odani
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Aoyama
authors.forename: Teruki
authors.initials: T
authors.lastname: Hamada
authors.forename: Masakuni
authors.initials: M
authors.lastname: Kori
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C000591345:3-(2-(3-chloro-5-fluorobenzyl)-1-benzothiophen-7-yl)-N-(2-methoxyethyl)benzamide; D014150:Antipsychotic Agents; D001549:Benzamides; D043562:Receptors, G-Protein-Coupled; D013876:Thiophenes; D008694:Methamphetamine