Syntheses of 4,6'-epoxymorphinan derivatives and their pharmacologies.
A modification of the message site in the skeleton of naltrexone was carried out to improve the potency and selectivity of the compound for an opioid receptor subtype. In the course of conversion, we synthesized 7-membered ring ether derivatives, which had an inserted OCH(2) group between 4- and 6-positions of morphinan skeleton. One of the 7-membered ring ether derivatives possessed more potent antagonistic activity than naltrexone for the mu opioid receptor. Another compound possessing 17-methyl group derived from noroxycodone may be a mu opioid receptor partial agonist and showed analgesic activity. We are currently examining the subtype selectivity of these compounds.
Nemoto
Toru
T
Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Tokyo 108-8641, Japan.
Fujii
Hideaki
H
Narita
Minoru
M
Miyoshi
Kan
K
Nakamura
Atsushi
A
Suzuki
Tsutomu
T
Nagase
Hiroshi
H
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006168:Guinea Pigs; D008024:Ligands; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship
D008024:Ligands; D009019:Morphinans; D011957:Receptors, Opioid; D019204:GTP-Binding Proteins