Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity

Tsuyoshi Saitoh; Kazunori Seki; Ryo Nakajima; Naoshi Yamamoto; Noriki Kutsumura; Yasuyuki Nagumo; Yoko Irukayama-Tomobe; Yasuhiro Ogawa; Yukiko Ishikawa; Ryuji Tanimura; Masashi Yanagisawa; Hiroshi Nagase

doi:10.1016/j.bmcl.2019.07.039

Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity

Bioorg Med Chem Lett. 2019 Sep 15;29(18):2655-2658. doi: 10.1016/j.bmcl.2019.07.039. Epub 2019 Jul 24.

Affiliations

¹ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
² Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
³ Pharmaceutical Research Laboratories, Toray Industries Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
⁴ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; R&D Center for Frontiers of Mirai in Policy and Technology (F-MIRAI), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁵ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan. Electronic address: [email protected].

PMID: 31375290
DOI: 10.1016/j.bmcl.2019.07.039

Abstract

The orexin 1 receptor (OX₁R) antagonists carrying a morphinan skeleton such as YNT-707 (2) and YNT-1310 (3) showed potent and extremely high selective antagonistic activity against OX₁R. In the course of our study of the essential structure of YNT-707 for high binding affinity against OX₁R, we prepared derivatives of 2 without the D- and 4,5-epoxy rings to clarify the roles of these structural determinants toward OX₁R antagonistic activity. The D- and 4,5-epoxy rings played important roles for the active orientation of the 17-sulfonamide and 6-amide side chains. Finally, we identified the simple structure required for selective OX₁R antagonistic activity in the complex morphinan skeleton, which is expected to be a useful scaffold for further design of OX₁R ligands.

Keywords: Morphinan; Nalfurafine; Orexin; Ring removal; YNT-707.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Humans
Molecular Structure
Morphinans / chemical synthesis
Morphinans / chemistry
Morphinans / pharmacology*
Orexin Receptor Antagonists / chemical synthesis
Orexin Receptor Antagonists / chemistry
Orexin Receptor Antagonists / pharmacology*
Orexin Receptors / metabolism*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

4,5-epoxymorphinan
Morphinans
Orexin Receptor Antagonists
Orexin Receptors
Sulfonamides
YNT-707