title: Design, synthesis, and structure-activity relationship of novel opioid κ receptor selective agonists: α-iminoamide derivatives with an azabicyclo[2.2.2]octene skeleton.
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.
authors.affiliation: 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.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Kitazawa
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nemoto
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Hirayama
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwai
authors.affiliation: 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.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Gouda
authors.affiliation: Laboratory of Physical Chemistry for Drug Design, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.affiliation: 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.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagasea
mesh_terms: D000577:Amides / Q000737:chemistry*; D001372:Aza Compounds / Q000737:chemistry / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D011485:Protein Binding; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001372:Aza Compounds; D001643:Bridged Bicyclo Compounds; D017473:Receptors, Opioid, kappa
keywords: Azabicyclo[2.2.2]octene skeleton; Nalfurafine; α-Iminoamide; κ agonist