Discovery of orexin 2 receptor selective and dual orexin receptor agonists based on the tetralin structure: Switching of receptor selectivity by chirality on the tetralin ring

Keita Iio; Tsuyoshi Saitoh; Ryuichiro Ohshita; Tsubasa Hino; Mao Amezawa; Yoshiaki Takayama; Yasuyuki Nagumo; Naoshi Yamamoto; Noriki Kutsumura; Yoko Irukayama-Tomobe; Yukiko Ishikawa; Ryuji Tanimura; Masashi Yanagisawa; Hiroshi Nagase

doi:10.1016/j.bmcl.2022.128555

Discovery of orexin 2 receptor selective and dual orexin receptor agonists based on the tetralin structure: Switching of receptor selectivity by chirality on the tetralin ring

Bioorg Med Chem Lett. 2022 Mar 15:60:128555. doi: 10.1016/j.bmcl.2022.128555. Epub 2022 Jan 17.

Affiliations

¹ Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
² International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
³ 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.
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, TX 75390, 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: 35051577
DOI: 10.1016/j.bmcl.2022.128555

Abstract

A novel series of 1-amino-tetralin derivatives were designed and synthesized based on the putative binding mode of the naphthalene-type orexin receptor agonist 5 and their agonist activities against orexin receptors were evaluated. The introduction of N-methyl-(3-methoxyphenyl)acetamide unit onto the 1-amino-tetralin skeleton remarkably enhanced the potency of the agonist. The asymmetric synthesis of 6 revealed that (-)-6 having a (S)-1-amino-tetralin skeleton showed a OX₂R selective agonist activity (EC₅₀ = 2.69 nM for OX₂R, OX₁R/OX₂R = 461) yet its enantiomer (R)-(+)-6 showed a potent OX_1/2R dual agonist activity (EC₅₀ = 13.5 nM for OX₁R, 0.579 nM for OX₂R, OX₁R/OX₂R = 23.3). These results suggested that upward orientation of the amide side chain against the tetralin scaffold (S-configuration) would be selective for OX₂R activation, and the downward orientation (R-configuration) would be significant for dual agonist activity. To our best knowledge, there have been no reports thus far that the stereochemistry of one carbon center on the agonist structure regulates the orexin receptor selectivity. Our results would provide important information for the development of OX₁R selective agonists.

Keywords: Agonist; Diarylsulfonamide; OX1R; OX2R; Orexin; Orexin receptor; Tetraline.

Publication types

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

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Orexin Receptors / agonists*
Structure-Activity Relationship
Tetrahydronaphthalenes / chemical synthesis
Tetrahydronaphthalenes / chemistry
Tetrahydronaphthalenes / pharmacology*

Substances

Orexin Receptors
Tetrahydronaphthalenes
tetralin