Synthesis of 6,14-epoxymorphinan derivatives and their pharmacologies.
A novel 6,14-epoxymorphinan benzamide derivative (NS22) that was previously reported showed opioid κ receptor agonistic activity and analgesic activity. The unsatisfactory κ selectivity of NS22 led us to synthesize its derivatives to improve the opioid κ receptor selectivity and the agonist activity. In the course of SAR of the various derivatives, 17-benzyl-6,14-epoxymorphinan derivatives (KNT-33, 53, 55, 80, 90, 133) were found to show high selectivities and affinities for the opioid κ receptor. In addition, KNT-33, 53, 55 showed dose-dependent analgesic effects in acetic acid writhing tests. Therefore, 17-benzyl substituents may play an important role for developing κ selectivity.
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Toru
T
Nemoto
Naoshi
N
Yamamoto
Akio
A
Watanabe
Hideaki
H
Fujii
Ko
K
Hasebe
Mayumi
M
Nakajima
Hidenori
H
Mochizuki
Hiroshi
H
Nagase
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000700:Analgesics; D001549:Benzamides; D004852:Epoxy Compounds; D009019:Morphinans; C540147:NS22 compound; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa