Drug design and synthesis of a novel kappa opioid receptor agonist with an oxabicyclo[2.2.2]octane skeleton and its pharmacology

Hiroshi Nagase; Akio Watanabe; Toru Nemoto; Noriyuki Yamaotsu; Kohei Hayashida; Mayumi Nakajima; Ko Hasebe; Kaoru Nakao; Hidenori Mochizuki; Shuichi Hirono; Hideaki Fujii

doi:10.1016/j.bmcl.2009.11.027

Drug design and synthesis of a novel kappa opioid receptor agonist with an oxabicyclo[2.2.2]octane skeleton and its pharmacology

Bioorg Med Chem Lett. 2010 Jan 1;20(1):121-4. doi: 10.1016/j.bmcl.2009.11.027. Epub 2009 Nov 13.

Authors

Hiroshi Nagase¹, Akio Watanabe, Toru Nemoto, Noriyuki Yamaotsu, Kohei Hayashida, Mayumi Nakajima, Ko Hasebe, Kaoru Nakao, Hidenori Mochizuki, Shuichi Hirono, Hideaki Fujii

Affiliation

¹ School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. nagaseh@pharm.kitasato-u.ac.jp

PMID: 19962305
DOI: 10.1016/j.bmcl.2009.11.027

Abstract

A conformational analysis of kappa opioid receptor agonists, TRK-820 and U-50,488H indicated an active conformation of TRK-820 in which the C-ring was in the boat form with the 14-OH interacting with the amide nitrogen. Based on the obtained active conformation of TRK-820, we designed and synthesized a novel kappa agonist KNT-63 with oxabicyclo[2.2.2]octane skeleton. KNT-63 showed profound antinociceptive effects via the kappa receptor which were as potent as that of TRK-820.

Publication types

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

MeSH terms

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / chemistry
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
Animals
Brain / metabolism
Bridged Bicyclo Compounds / chemical synthesis
Bridged Bicyclo Compounds / chemistry*
Bridged Bicyclo Compounds / pharmacology
Bridged-Ring Compounds / chemical synthesis*
Bridged-Ring Compounds / chemistry
Bridged-Ring Compounds / pharmacology
Drug Design
Guinea Pigs
Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
Heterocyclic Compounds, 4 or More Rings / chemistry
Heterocyclic Compounds, 4 or More Rings / pharmacology
Molecular Conformation
Morphinans / chemistry
Morphinans / pharmacology
Receptors, Opioid, kappa / agonists*
Receptors, Opioid, kappa / metabolism
Spiro Compounds / chemistry
Spiro Compounds / pharmacology
Structure-Activity Relationship

Substances

Bridged Bicyclo Compounds
Bridged-Ring Compounds
Heterocyclic Compounds, 4 or More Rings
KNT 63
Morphinans
Receptors, Opioid, kappa
Spiro Compounds
TRK 820
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer