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.
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.