Essential structure of orexin 1 receptor antagonist YNT-707: Conversion of the 16-cyclopropylmethyl group to the 16-sulfonamide group in d-nor-nalfurafine derivatives

Koki Katoh; Noriki Kutsumura; Naoshi Yamamoto; Yasuyuki Nagumo; Tsuyoshi Saitoh; Yukiko Ishikawa; Yoko Irukayama-Tomobe; Ryuji Tanimura; Masashi Yanagisawa; Hiroshi Nagase

doi:10.1016/j.bmcl.2022.128550

Essential structure of orexin 1 receptor antagonist YNT-707: Conversion of the 16-cyclopropylmethyl group to the 16-sulfonamide group in d-nor-nalfurafine derivatives

Bioorg Med Chem Lett. 2022 Mar 1:59:128550. doi: 10.1016/j.bmcl.2022.128550. Epub 2022 Jan 15.

Affiliations

¹ Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
² Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
³ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
⁴ Pharmaceutical Research Laboratories, Toray Industries, Inc., 10-1, Tebiro 6-choume, Kamakura, Kanagawa 248-8555, Japan.
⁵ 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, TX75390, USA.
⁶ Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: nagase.hiroshi.gt@u.tsukuba.ac.jp.

PMID: 35041942
DOI: 10.1016/j.bmcl.2022.128550

Abstract

The five-membered D-ring nalfurafine (d-nor-nalfurafine) derivatives with a 16-sulfonamide group were synthesized. Conversion of the 16-cyclopropylmethyl group to the 16-benzenesulfonamide group in the d-nor-nalfurafine derivatives drastically improved the orexin 1 receptor (OX₁R) antagonist activities. The intramolecular hydrogen bond between the 14-hydroxy and the 16-sulfonamide groups may play an important role in increasing the probability that the 6-amide group would be located at the lower side of the C-ring, leading to an active conformation for OX₁R. The assay results and the conformational analyses of the 14-OH, 14-H, and 14-dehydrated d-nor-nalfurafine derivatives suggested that the 14- and 16-substituents of the d-nor-nalfurafine derivatives had a greater effect on the affinities for the OX₁R than did the 14- and 17-substituents of nalfurafine derivatives.

Keywords: Antagonist; Morphinan; Nalfurafine; Orexin; Sulfonamide.

Publication types

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

MeSH terms

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

Substances

Morphinans
Orexin Receptor Antagonists
Orexin Receptors
Spiro Compounds
Sulfonamides
YNT-707
TRK 820