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 OHM10579 partially substituted for nalbuphine. In 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-abstinent monkeys, morphine reversed naltrexone-lever responding, an effect attenuated by OHM10579. The shift to the right in the morphine dose-effect 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 duration of action than mirfentanil. In a warm-water tail-withdrawal procedure, 10 and 17.8 mg/kg of OHM10579 had antinociceptive effects that were not antagonized by naltrexone. Morphine decreased breathing in air to 48%, whereas the maximal decrease with OHM10579 was to 75% of control. OHM10579 attenuated hyperventilation induced by 5% CO2 and partially antagonized the respiratory-depressant effects of morphine. OHM10579 can be classified as a low-efficacy mu-opioid agonist with some nonopioid actions. These results indicate that the pharmacology of the mirfentanil isotope OHM10579 is similar to that of mirfentanil, but that OHM10579 might have a longer duration of action.
Department of Pharmacology and Neuroscience Center of Excellence, Louisiana State University Medical Center, New Orleans 70112-1393, USA.
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S
Lelas
L R
LR
Gerak
L K
LK
Landers
M R
MR
Brandt
J R
JR
Bagley
L L
LL
Brockunier
C P
CP
France
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003903:Deuterium; D004192:Discrimination, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D009266:Nalbuphine / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D015656:Respiratory Mechanics / Q000187:drug effects
D000700:Analgesics; D009292:Narcotic Antagonists; C114533:OHM10579; D009271:Naltrexone; D003903:Deuterium; D009266:Nalbuphine; C069209:mirfentanil; D005283:Fentanyl