Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities

Kohei Hayashida; Shigeto Hirayama; Takashi Iwai; Yoshikazu Watanabe; Toshihiro Takahashi; Junichi Sakai; Eriko Nakata; Tomio Yamakawa; Hideaki Fujii; Hiroshi Nagase

doi:10.1016/j.bmcl.2017.04.059

Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities

Bioorg Med Chem Lett. 2017 Jun 15;27(12):2742-2745. doi: 10.1016/j.bmcl.2017.04.059. Epub 2017 Apr 19.

Authors

Affiliations

¹ Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan; Discovery Research Laboratories, Nippon Chemiphar Co., Ltd., 1-22, Hikokawado, Misato, Saitama 341-0005, 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 Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan; Laboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
⁴ Discovery Research Laboratories, Nippon Chemiphar Co., Ltd., 1-22, Hikokawado, Misato, Saitama 341-0005, 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.
⁶ Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan; International Institute for Integrative Sleep Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.

PMID: 28522254
DOI: 10.1016/j.bmcl.2017.04.059

Abstract

We recently reported oxazatricyclodecane derivatives 1 as δ opioid receptor (DOR) agonists having a novel chemotype, but their DOR agonistic activities were relatively low. Based on the working hypothesis that the dioxamethylene moiety in 1 may be an accessory site and that it may interfere with the sufficient conformational change of the receptor required for exerting the full agonistic responses, we designed and synthesized new oxazatricyclodecane derivatives 2-4 lacking the dioxamethylene moiety. As we expected, the designed compounds 2-4 showed pronouncedly improved agonistic activities for the DOR. Compound 2a with the 17-cyclopropylmethyl substituent was a potent agonist with the highest selectivity for the DOR and was expected to be a lead compound for novel and selective DOR agonists.

Keywords: Accessory site; DOR agonist; Dioxamethylene moiety; Opioid; Oxazatricyclodecane structure.

Publication types

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

MeSH terms

Dose-Response Relationship, Drug
Heterocyclic Compounds, Bridged-Ring / chemical synthesis
Heterocyclic Compounds, Bridged-Ring / chemistry
Heterocyclic Compounds, Bridged-Ring / pharmacology*
Humans
Molecular Structure
Receptors, Opioid, delta / agonists*
Structure-Activity Relationship

Substances

Heterocyclic Compounds, Bridged-Ring
Receptors, Opioid, delta