Opioid ligands having delayed long-term antagonist activity: potential pharmacotherapies for opioid abuse.

Buprenorphine is a partial agonist at the micro -opioid receptor with long duration of action and also exhibits delayed antagonist activity. Buprenorphine is finding increasing use as a treatment agent for opioid abuse, though its low efficacy is not well tolerated by all addicts. There is interest in developing a higher efficacy version of buprenorphine and in this mini-review some of the ligands recently discovered, that share with buprenorphine a profile of agonism followed by delayed antagonism, are discussed.

Antinociceptive activity of pentamorphone, a 14-beta-aminomorphinone derivative, compared to fentanyl and morphine.

The analgesic potency of pentamorphone, a 14-beta-aminomorphinone derivative, was compared to that of fentanyl and morphine by examining quantal dose-effect curves generated from data obtained in the mouse hot plate, rabbit tooth-pulp, and dog tail clamp tests. Onset and duration of antinociceptive effects were also compared. The ED50 values (mg/kg) were determined in mice for pentamorphone (0.0039), fentanyl (0.016), and morphine (7.3). In the rabbit tooth pulp test the ED50 values were 0.0009 mg/kg for pentamorphone, 0.0074 mg/kg for fentanyl, and 1.1 mg/kg for morphine; in the dog tail clamp test these values were 0.012 mg/kg for pentamorphone and 0.018 mg/kg for fentanyl. Duration of action (defined as the time until response to tooth pulp stimulation declined to 50% of maximum possible effect [MPE]) was 10 min with twice the IV ED50 for pentamorphone in mice. This duration was similar to that of the equipotent dose of fentanyl but much shorter than the duration of an equipotent potent dose of morphine (60 min). The duration in rabbits of the ED98 (IV) dose of pentamorphone was 65 min compared to 35 min for an equipotent dose of fentanyl and 200 min for morphine. Intramuscular doses of pentamorphone had significantly faster onset and shorter duration times than equipotent doses of morphine in both mice and rabbits. Pretreatment with naloxone in mice and rabbits attenuated the development of the antinociceptive effects of pentamorphone. This study shows that pentamorphone is a potent analgesic with a duration of action similar to that of fentanyl.

Opioid agonist and antagonist activities of peripherally selective derivatives of naltrexamine and oxymorphamine.

A series of beta-naltrexamine and beta-oxymorphamine derivatives that contain ionizable moieties coupled to the 6 beta-amino group were synthesized in an effort to develop antagonists and agonists that have negligible access into the central nervous system (CNS). Among the beta-naltrexamine derivatives 1-7, all displayed partial agonism on the guinea pig ileal longitudinal muscle preparation except for aspartyl derivative 6, which was a full agonist with activity in the range of morphine. The beta-oxymorphamine derivatives 8-12 were all full agonists with potencies ranging from 1.5 to 6.1 times that of morphine. Among the compounds evaluated in mice for antinociceptive or opioid antagonist activities, aspartyl derivative 6 possessed the greatest difference between peripheral (po or iv) and icv equiactive antagonist doses. Compared to naltrexone, 6 was greater than 100 times more potent by the icv route, but 6000-10,000 times less potent when administered po or icv. The present study suggests that zwitterionic groups are highly effective in preventing penetration of ligands into the CNS. Such ligands may be useful pharmacologic tools for investigation of peripheral opioid mechanisms. Moreover, they could find clinical applications when the central actions are unwanted.

A spirohydantoin derivative of oxymorphone: an agonist with delayed antagonist activity.

We have synthesized a novel derivative of oxymorphone, oxymorphone-6 alpha-spirohydantoin. The derivative was less toxic in mice than the parent compound and it showed a significant anticonvulsive activity. It exerted agonist effects in doses lower than those of morphine and its agonist effects were longer lasting. Furthermore, both oxymorphone and the 6-spirohydantoin showed definite antagonist properties 48 hr later: they prevented analgesic effects of morphine. The antagonist effects of the derivative persisted for a week.