Design and synthesis of novel delta opioid receptor agonists and their pharmacologies.
We re-examined the accessory site of the 4,5-epoxymorphinan skeleton by camdas conformational analysis in an effort to deign novel delta opioid receptor antagonists. We synthesized three novel compounds (SN-11, 23 and 28) with a 10-methylene bridge and without a 4,5-epoxy ring. Among them, compounds SN-23 (17-isobutyl derivative) and SN-28 (17-methyl derivative) showed very strong agonist activity (over 10 times more than TAN-67). SN-28 also showed high delta selectivity. The delta agonist activity of SN-23 was weaker than that of SN-28, but in terms of the delta selectivity, SN-23 was higher than that of SN-28. These unexpected results indicated that the 4,5-epoxy ring, but not the 10-methylene bridge, was an accessory site in delta opioid receptor agonists.
Nagase
Hiroshi
H
Department of Medicinal Chemistry, Kitasato University, Shirokane, Minato-ku, Tokyo, Japan. nagaseh@pharm.kitasato-u.ac.jp
Osa
Yumiko
Y
Nemoto
Toru
T
Fujii
Hideaki
H
Imai
Masayuki
M
Nakamura
Takashi
T
Kanemasa
Toshiyuki
T
Kato
Akira
A
Gouda
Hiroaki
H
Hirono
Shuichi
S
D015195:Drug Design; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism
C496139:4,5-epoxymorphinan; D009019:Morphinans; D017465:Receptors, Opioid, delta; C541547:SN-23 compound; C541548:SN-28 compound; D009271:Naltrexone; C055382:naltrindole