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Paper | Special issue | Vol 103, No. 2, 2021, pp.929-951
Published online, 1st March, 2021
DOI: 10.3987/COM-20-S(K)63
Design and Synthesis of Novel Orexin Antagonists via Structural Simplification of the Morphinan Skeleton

Sayaka Ohrui,* Yoko Irukayama-Tomobe, Yukiko Ishikawa, Masashi Yanagisawa, and Hiroshi Nagase

*C1232 Kanagawa Science Park R & D Building, Research Foundation ITSUU Laboratory, 3-2-1 Sakado, Takatsu-ku, 213-0012 Kawasaki, Kanagawa, Japan


Herein, we report novel orexin antagonists with a spiro-type piperidine skeleton designed and synthesized via removal of the unnecessary sites of orexin 1 receptor (OX1R) antagonists with a morphinan skeleton for binding to OX1R. In addition, while decahydroisoquinoline compounds with an A-ring did not show antagonistic activity for OX1R, spiro-type piperidine compounds with a dihydroindene structure showed antagonistic activities. This suggests that the lipophilic site corresponding to the A-ring of the morphinan skeleton is important for determining the antagonistic activity toward OX1R.