PHARMACOLOGICAL PROFILE OF A DEUTERIUM-SUBSTITUTED MIRFENTANIL DERIVATIVE, OHM10579, IN RHESUS-MONKEYS

The discriminative stimulus, respiratory, and antinociceptive effects of OHM10579, an isotopic isomer of mirfentanil, were characterized in rhesus monkeys. In monkeys discriminating nalbuphine, 0.32 mg/kg of OH M10579 partially substituted for nalbuphine. Tn monkeys treated daily with 3.2 mg/kg of morphine and discriminating 0.01 mg/kg of naltrexone , 0.32 mg/kg of OHM10579 substituted for naltrexone. In morphine-absti nent monkeys, morphine reversed naltrexone-lever responding, an effect attenuated by OHM10579. The shift to the right in the morphine dose-e ffect curve was greater 2 h after 0.32 mg/kg of OHM10579 compared to 0 .32 mg/kg of mirfentanil, indicating that OHM10579 has a longer durati on of action than mirfentanil. In a warm-water tail-withdrawal procedu re, 10 and 17.8 mg/kg of OHM10579 had antinociceptive effects that wer e not antagonized by naltrexone. Morphine decreased breathing in air t o 48%, whereas the maximal decrease with OHM10579 was to 75% of contro l. OHM10579 attenuated hyperventilation induced by 5% CO2 and partiall y antagonized the respiratory-depressant effects of morphine. OHM10579 can be classified as a low-efficacy mu-opioid agonist with some nonop ioid actions. These results indicate that the pharmacology of the mirf entanil isotope OHM10579 is similar to that of mirfentanil, but that O HM10579 might have a longer duration of action. (C) 1998 Elsevier Scie nce Inc.