Design and synthesis of novel orexin 2 receptor agonists with a 1,3,5‑trioxazatriquinane skeleton

Mao Amezawa; Naoshi Yamamoto; Yasuyuki Nagumo; Noriki Kutsumura; Yukiko Ishikawa; Masashi Yanagisawa; Hiroshi Nagase; Tsuyoshi Saitoh

doi:10.1016/j.bmcl.2023.129151

Design and synthesis of novel orexin 2 receptor agonists with a 1,3,5‑trioxazatriquinane skeleton

Bioorg Med Chem Lett. 2023 Feb 15:82:129151. doi: 10.1016/j.bmcl.2023.129151. Epub 2023 Jan 20.

Authors

Mao Amezawa¹, Naoshi Yamamoto², Yasuyuki Nagumo², Noriki Kutsumura³, Yukiko Ishikawa², Masashi Yanagisawa⁴, Hiroshi Nagase⁵, Tsuyoshi Saitoh⁶

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 (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 (IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
⁴ International Institute for Integrative Sleep Medicine (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, US.
⁵ 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 (IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: nagase.hiroshi.gt@u.tsukuba.ac.jp.
⁶ International Institute for Integrative Sleep Medicine (IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: saito.tsuyoshi.gf@u.tsukuba.ac.jp.

PMID: 36690040
DOI: 10.1016/j.bmcl.2023.129151

Abstract

A novel series of 1,3,5‑trioxazatriquinane with multiple effective residues (TriMER) derivatives with amino-methylene side chains was designed and synthesized based on the docking-simulation results between orexin receptors (OXRs) and TriMER-type OXR antagonists. In vitro screening against orexin receptors identified six TriMER derivatives with a cis side-chain configuration, and, among these, 20d and 28d showed full agonist activity against OX₂R at a concentration of 10 µM. To determine the absolute stereochemistry of these hit compounds, we also conducted the first asymmetric synthesis of a 1,3,5‑trioxazatriquinane skeleton using a Katsuki-Sharpless asymmetric epoxidation as the key reaction and obtained a set of the individual stereoisomers. After evaluating their activity, (+)-20d (EC₅₀ = 3.87 μM for OX₂R) and (+)-28d (EC₅₀ = 1.62 μM for OX₂R) were determined as eutomers for OX₂R agonist activity. Our results provide a new class of skeleton consisting of an (R)-1,3,5‑trioxazatriquinane core with flexible methylene linkers and hydrophobic substituents at the terminals of the side chains via carbamates/sulfonamides as OX₂R agonists.

Keywords: 1,3,5-Trioxazatriquinane; Asymmetric synthesis; OX(2)R agonist; Orexin receptor; TriMER.

Publication types

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

MeSH terms

Orexin Receptor Antagonists* / pharmacology
Orexin Receptors / agonists
Orexins
Skeleton*

Substances

Orexin Receptors
Orexins
1,3,5-trioxazatriquinane
Orexin Receptor Antagonists