Opioid and Non-opioid Actions of Novel Fentanyl Derivatives in Rhesus Monkey Analgesia and Mouse Vas Deferentia Studies
Four fentanyl derivatives recently developed in the 4-(heteroanilido)-piperidine series (ANQ 3463, 3326, 3296 and 3295) have the potential to be clinically important analgesics. All test compounds were studied in the rhesus monkey (Macaca mulatta) to evaluate the analgesic effects of each compound. Preliminary studies of drugs were also made in isolated mouse vas deferentia because it is a simpler model for drug classification than the whole animal model. In analgesia studies, all fentanyl derivatives were potent analgesics with little associated respiratory or cardiac depression. In addition, test compounds antagonized the respiratory depressant effects of large doses of alfentanil. Results of this study demonstrate that small structural changes in the parent compound fentanyl produce significant differences in the agonist and antagonist actions of these compounds. For example, opioid analgesia was observed with ANQ 3463, that was attenuated by naltrexone in a manner consistent with mu receptor mediation, while ANQ 3326 and ANQ 3296 produced both opioid and non-opioid analgesia. In addition, acute doses of both compol:lnds antagonized the analgesic effects of alfentanil. ANQ 3295 had only non-opioid agonist effects and opioid antagonist effects in analgesia studies. ANQ 3295 in small doses was similar to the opioid antagonist naltrexone. Results obtained in the isolated mouse vas deferens studies support the opioid and non-opioid characterizations of ANQ 3463, 3326 and 3296 found in the analgesia studies. However, in isolated tissue ANQ 3295 produced some opioid agonist actions which were not observed in analgesia studies.
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