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

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.
Yoshikazu Watanabe 1,  Shota Kitazawa 2,  Hideaki Fujii 2,  Toru Nemoto 2,  Shigeto Hirayama 2,  Takashi Iwai 2,  Hiroaki Gouda 3,  Shuichi Hirono 4,  Hiroshi Nagasea 5
Affiliations

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.

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