Synthesis and pharmacological activity of sulfate conjugates at 6-position of N-substituted normorphine derivatives.
Three pairs of N-substituted normorphine derivatives and the sulfate conjugates at the 6-position were tested for the analgesic and antagonistic activities and the development of physical dependence in mice. The compounds examined were nalorphine, nalorphine-6-sulfate (N-6-S), N-cyclopropylmethylnormorphine (CPN), N-cyclopropylmethylnormorphine-6-sulfate (C-6-S), N-dimethylallylnormorphine (DMN) and N-dimethylallylnormorphine-6-sulfate (D-6-S). The latter two pairs were newly synthesized. The analgesic activity of C-6-S and D-6-S was equipotent to that of CPN and DMN by the acetic acid writhing test on the s.c. injection, and the activity of N-6-S was about 2 times more potent than that of nalorphine. The antagonistic activity of N-6-S, C-6-S and D-6-S to morphine analgesia was higher than that of the parent compounds by the tail pinch test on i.c.v. injection. A withdrawal sign was seen in mice treated chronically with CPN, C-6-S and N-6-S by challenge with naloxone, whereas the mice treated with DMN, D-6-S and nalorphine showed no such sign. The effect of sulfation at the 6-position on the development of physical dependence was not well associated with the effect on agonistic and antagonistic activities.
Hirano
T
T
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Oguri
K
K
Yoshimura
H
H
D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009022:Morphine Derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology
D000700:Analgesics; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; C010616:normorphine