Design, synthesis, and structure-activity relationship of novel opioid κ receptor selective agonists: α-iminoamide derivatives with an azabicyclo[2.2.2]octene skeleton

Yoshikazu Watanabe; Shota Kitazawa; Hideaki Fujii; Toru Nemoto; Shigeto Hirayama; Takashi Iwai; Hiroaki Gouda; Shuichi Hirono; Hiroshi Nagasea

doi:10.1016/j.bmcl.2014.09.029

Design, synthesis, and structure-activity relationship of novel opioid κ receptor selective agonists: α-iminoamide derivatives with an azabicyclo[2.2.2]octene skeleton

Bioorg Med Chem Lett. 2014 Nov 1;24(21):4980-3. doi: 10.1016/j.bmcl.2014.09.029. Epub 2014 Sep 21.

Authors

Yoshikazu Watanabe¹, Shota Kitazawa², Hideaki Fujii², Toru Nemoto², Shigeto Hirayama², Takashi Iwai², Hiroaki Gouda³, Shuichi Hirono⁴, Hiroshi Nagasea⁵

Affiliations

¹ 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-shi, Saitama 341-0005, Japan.
² 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; Laboratory of Physical Chemistry for Drug Design, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
⁴ Laboratory of Physical Chemistry for Drug Design, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
⁵ 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: 25283554
DOI: 10.1016/j.bmcl.2014.09.029

Abstract

The α-iminoamide derivative, 4b was designed and synthesized as a novel agonist selective for the opioid κ receptor. The amide was constrained to an orientation horizontal to the F-ring of the azabicyclo[2.2.2]octane skeleton, which remarkably improved its affinity, selectivity, and agonistic activity for the κ receptor. This finding was newly established by chemical modification of the nitrogen atom at the 8-position in the azabicyclo[2.2.2]octane skeleton. This modification would never have been found with KNT-63, a derivation of oxabicyclo[2.2.2]octane. These results may provide valuable information for the future development of novel κ selective agonists.

Keywords: Azabicyclo[2.2.2]octene skeleton; Nalfurafine; α-Iminoamide; κ agonist.

MeSH terms

Amides / chemistry*
Aza Compounds / chemistry
Aza Compounds / pharmacology*
Bridged Bicyclo Compounds / chemistry
Bridged Bicyclo Compounds / pharmacology*
Drug Design*
Humans
Molecular Conformation
Molecular Structure
Protein Binding
Receptors, Opioid, kappa / agonists*
Structure-Activity Relationship

Substances

Amides
Aza Compounds
Bridged Bicyclo Compounds
Receptors, Opioid, kappa