Morphinan derivatives with an oxabicyclo[3.2.1]octane structure as dual agonists toward δ and κ opioid receptors

Yuka Uenohara; Saori Tsumura; Shigeto Hirayama; Eika Higashi; Yurie Watanabe; Hiroaki Gouda; Hiroshi Nagase; Hideaki Fujii

doi:10.1016/j.bmc.2021.116552

Morphinan derivatives with an oxabicyclo[3.2.1]octane structure as dual agonists toward δ and κ opioid receptors

Bioorg Med Chem. 2022 Jan 1:53:116552. doi: 10.1016/j.bmc.2021.116552. Epub 2021 Dec 4.

Authors

Yuka Uenohara¹, Saori Tsumura¹, Shigeto Hirayama², Eika Higashi¹, Yurie Watanabe³, Hiroaki Gouda³, Hiroshi Nagase⁴, Hideaki Fujii⁵

Affiliations

¹ Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
² Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan; Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
³ School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
⁴ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
⁵ Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan; Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: fujiih@pharm.kitasato-u.ac.jp.

PMID: 34894610
DOI: 10.1016/j.bmc.2021.116552

Abstract

The κ opioid receptor (KOR) is one of the promising targets to develop analgesics lacking morphine like side effects. To seek a novel KOR agonist we designed 6-amide derivatives with an oxabicyclo[3.2.1]octane structure based on a proposed active conformation of a selective KOR agonist nalfurafine. All the synthesized compounds strongly bound to the KOR and some compound showed KOR selectivities. 6R-Amides were more potent and efficacious KOR agonists than the corresponding 6S-isomers. However, most 6-amide derivatives were partial KOR agonist. Conformational analyses of 6R- and 6S-amide derivatives and nalfurafine well accounted for the difference of KOR agonistic activities between two diastereomers. Surprisingly, the tested N-H amides were full δ opioid receptor (DOR) agonists. Among the tested compounds 7a with benzamide moiety was the most potent dual DOR/KOR agonist. On the other hand, 6S-phenylacetamide 8b was potent full DOR agonist with less efficacious agonist activity for the μ receptor and KOR. 6-Amide derivatives with an oxabicyclo[3.2.1]octane structure were expected to be a promising fundamental skeleton for the dual DOR/KOR agonists and/or selective DOR agonists.

Keywords: DOR agonist; Dual agonist; KOR agonist; Opioid; Oxabicyclo[3.2.1]octane structure.

MeSH terms

Analgesics / chemical synthesis
Analgesics / chemistry
Analgesics / pharmacology*
Dose-Response Relationship, Drug
Humans
Molecular Structure
Morphinans / chemical synthesis
Morphinans / chemistry
Morphinans / pharmacology*
Receptors, Opioid, delta / agonists*
Receptors, Opioid, kappa / agonists*
Structure-Activity Relationship

Substances

Analgesics
Morphinans
Receptors, Opioid, delta
Receptors, Opioid, kappa