Synthesis and Pharmacological Activity of Sulfate Conjugates at 6-Position of N-Substituted Normorphine Derivatives

• Published in: Chemical & pharmaceutical bulletin Vol. 39; no. 8; pp. 2000 - 2004
• Main Authors: HIRANO, Takaaki, OGURI, Kazuta, YOSHIMURA, Hidetoshi
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 1991; Maruzen; Japan Science and Technology Agency
• Subjects: analgesic activity; Analgesics - chemical synthesis; Analgesics - pharmacology; Animals; antagonistic activity; Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Male; Mice; Mice, Inbred Strains; Morphine Derivatives - chemical synthesis; Morphine Derivatives - pharmacology; N-cyclopropylmethylnormorphine; N-dimethylallylnormorphine; nalorphine; Narcotic Antagonists - chemical synthesis; Narcotic Antagonists - pharmacology; opioid; Organic chemistry; physical dependence; Preparations and properties; sulfate conjugate; Drug; Pharmacological activity; Oxygen heterocycle; Chemical synthesis; Biological activity
• DOI: 10.1248/cpb.39.2000
• ISSN: 0009-2363

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.