Synthesis of N-isobutylnoroxymorphone from naltrexone by a selective cyclopropane ring opening reaction.
Selective ring opening reaction of the N-cyclopropylmethyl group in naltrexone (1d) was effected in the presence of platinum (IV) oxide and hydrobromic acid under a hydrogen atmosphere at rt to selectively afford N-isobutyl derivative 10. The binding affinity of N-i-Bu derivative 10 for opioid receptors was 11-17 times less than that of the corresponding N-CPM compound, naltrexone (1d). However, compound 10 showed dose-dependent analgesic effects. Contrary to expectations based on previous structure-activity relationship studies for a series of N-substituted naltrexone derivatives that compound 10 would be an opioid antagonist, 10 showed dose-dependent analgesia in the mouse acetic acid writhing test (ED(50): 5.05 mg/kg, sc), indicating it was an opioid agonist. This finding may have a great influence on the drug design of opioid agonists.
Fujii
Hideaki
H
School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Osa
Yumiko
Y
Ishihara
Marina
M
Hanamura
Shinichi
S
Nemoto
Toru
T
Nakajima
Mayumi
M
Hasebe
Ko
K
Mochizuki
Hidenori
H
Nagase
Hiroshi
H