Design and synthesis of novel orexin 2 receptor agonists based on naphthalene skeleton. (1st March 2022)

• Record Type: Journal Article
• Authors: Hino, Tsubasa; Saitoh, Tsuyoshi; Nagumo, Yasuyuki; Yamamoto, Naoshi; Kutsumura, Noriki; Irukayama-Tomobe, Yoko; Ishikawa, Yukiko; Tanimura, Ryuji; Yanagisawa, Masashi; Nagase, Hiroshi
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 59(2022)
• Publication Date: 2022-03-01
• Subjects: Orexin -- Orexin receptor -- GPCR -- OX1R -- OX2R -- Agonist -- Naphthalene -- Conformational restriction; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128530
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A novel series of naphthalene derivatives were designed and synthesized based on the strategy focusing on the restriction of the flexible bond rotation of OX2 R selective agonist YNT-185 (1 ) and their agonist activities against orexin receptors were evaluated. The 1, 7-naphthalene derivatives showed superior agonist activity than 2, 7-naphthalene derivatives, suggesting that the bent form of 1 would be favorable for the agonist activity. The conformational analysis of 1, 7-naphthalene derivatives indicated that the twisting of the amide unit out from the naphthalene plane is important for the enhancement of activity. The introduction of a methyl group on the 2-position of 1, 7-naphthalene ring effectively increased the activity, which led to the discovery of the potent OX2 R agonist 28c (EC50 = 9.21 nM for OX2 R, 148 nM for OX1 R). The structure–activity relationship results were well supported by a comparison of the docking simulation results of the most potent derivative 28c with an active state of agonist-bound OX2 R cryo-EM SPA structure. These results suggested important information for understanding the active conformation and orientation of pharmacophores in the orexin receptor agonists, which is expected as a chemotherapeutic agent for the treatment of narcolepsy.