Drug design and synthesis of a novel kappa opioid receptor agonist with an oxabicyclo[2.2.2]octane skeleton and its pharmacology.
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.
Nagase
Hiroshi
H
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. nagaseh@pharm.kitasato-u.ac.jp
Watanabe
Akio
A
Nemoto
Toru
T
Yamaotsu
Noriyuki
N
Hayashida
Kohei
K
Nakajima
Mayumi
M
Hasebe
Ko
K
Nakao
Kaoru
K
Mochizuki
Hidenori
H
Hirono
Shuichi
S
Fujii
Hideaki
H
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006168:Guinea Pigs; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D009019:Morphinans / Q000737:chemistry / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D006576:Heterocyclic Compounds, 4 or More Rings; C549131:KNT 63; D009019:Morphinans; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C111212:TRK 820; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer