n-(cyclobutylmethyl)-8-beta-methyl-6-methylenemorphinan-3-ol and Morphine-Dependence

The ability of four opiate partial agonists (buprenorphine, xorphanol, nalbuphine and butorphanol) to produce antinociception and morphine-like physical dependence was examined in the rat. For comparative purposes, morphine was also tested. Dose-response curves were constructed using the rat tail pressure test for analgesia which indicated a rank order of potency of buprenorphine much greater than morphine greater than butorphanol greater than xorphanol = nalbuphine. Assessment of primary physical dependence liability was made using the technique of chronic intraperitoneal infusion followed by precipitation of abstinence with the opiate antagonist, naloxone. The results clearly indicate that buprenorphine was not only the most potent antinociceptive agent, but also possessed the lowest incidence of physical dependence as indicated by precipitated abstinence signs. The other opiates were very much weaker as antinociceptive agents and all produced clear signs of physical dependence.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Butorphanol; Humans; Male; Morphinans; Morphine; Morphine Dependence; Nalbuphine; Nociceptors; Rats; Rats, Inbred Strains

Series of N-(cyclopropylmethyl) (P series) or N-(cyclobutylmethyl) (B series) 3-methoxy (1) or 3-hydroxy (2) morphinan-6-ones with hydrogen (a), methyl (b), or ethyl (c) groups in the 8 beta position were converted to the 6-methylene compounds 3 or 4 by reaction with Ph3P = CH2. One member of this new series, N-(cyclobutylmethyl)-8 beta-methyl-6-methylenemorphinan-3-ol (4Bb), had potent mixed agonist-narcotic antagonist properties and, in contrast to the previously studied 6-oxo compound 2Bb, did not substitute for morphine in dependent rats or monkeys.

Topics: Analgesics; Animals; Chemical Phenomena; Chemistry; Haplorhini; Humans; Mice; Morphinans; Morphine Dependence; Narcotic Antagonists; Rats; Reaction Time; Substance Withdrawal Syndrome