Mirfentanil: pharmacological profile of a novel fentanyl derivative with opioid and nonopioid effects.
Mirfentanil [N-(2-pyrazinyl)-N-(1-phenethyl-4-piperidinyl)-2-furamide] was studied for its binding affinity in isolated neuronal membranes, and for its effects in vivo. In binding to opioid receptors in monkey brain membranes, mirfentanil was much more selective for mu sites (7.99 nM) than for either kappa (1428 nM) or delta (480 nM) sites as measured by displacement of [3H]DAMGO. [3H]U-69.593 or [3H]DPDPE, respectively. In morphine-treated pigeons discriminating among naltrexone, saline and morphine, mirfentanil failed to substitute for either training drug; in morphine-abstinent pigeons, mirfentanil reversed responding on the naltrexone key (i.e., reversed withdrawal). In morphine-treated monkeys discriminating between saline and naltrexone, mirfentanil substituted completely for naltrexone, and this effect was attenuated by an acute injection of morphine; mirfentanil also attenuated the withdrawal-reversing effects of alfentanil in morphine-abstinent monkeys. Administered i.v., mirfentanil maintained rates of self-administration responding only slightly below rates maintained by alfentanil, and this effect of mirfentanil was antagonized by quadazocine. Small doses of mirfentanil (0.032-0.32 mg/kg) antagonized the analgesic effects of alfentanil; larger doses of mirfentanil both antagonized the analgesic effects of alfentanil and produced analgesic effects when administered alone. The analgesic effects of mirfentanil were not attenuated by large doses of opioid antagonists. Mirfentanil had modest respiratory depressant effects that were not altered by quadazocine; however, mirfentanil antagonized the respiratory depressant effects of large doses of alfentanil. Both in vivo and in vitro, mirfentanil appears to have selectivity for opioid mu receptors. Moreover, at doses larger than those which exert opioid effects, mirfentanil has nonopioid analgesic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
France
C P
CP
Department of Pharmacology, University of Michigan, Ann Arbor.
Winger
G
G
Medzihradsky
F
F
Seggel
M R
MR
Rice
K C
KC
Woods
J H
JH
D015760:Alfentanil / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D010856:Columbidae; D004193:Discrimination Learning / Q000187:drug effects; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects*; D017450:Receptors, Opioid, mu; D012119:Respiration / Q000187:drug effects; D012646:Self Administration; D013329:Structure-Activity Relationship
D000700:Analgesics; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D015760:Alfentanil; D009271:Naltrexone; D009020:Morphine; C069209:mirfentanil; D005283:Fentanyl