Signal transduction efficacy of the highly potent mu opioid agonist 14-methoxymetopon.
In search of a truly high-efficacy (i.e., tau > 100) mu opioid analgesic, we determined the efficacy (tau) and apparent in vivo affinity (KA) of the high-potency alkoxymorphinan 14-methoxymetopon. However, in the present study, 14-methoxymetopon's efficacy proved to be only 1.5-fold higher than that of morphine (tau, 19 vs. 12). KA values were 2,900 nmol/kg for 14-methoxymetopon and 46,000 nmol/kg for morphine (Ki for [3H]DAMGO binding, 0.33 vs 3.4 nmol/l). Thus, the 24-fold higher potency of methoxymetopon could be fully accounted for by its 16-fold higher apparent in vivo affinity and its only 1.5-fold higher efficacy. Furthermore, the 10-fold higher affinity of 14-methoxymetopon for the mu opioid receptor - as previously determined in radioligand binding assays - was confirmed in the present behavioral tests of thermal antinociception.
Zernig
G
G
Department of Psychiatry, University of Innsbruck, Austria. gerald.zernig@uibk.ac.at
Saria
A
A
Krassnig
R
R
Schmidhammer
H
H
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D006358:Hot Temperature; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D009022:Morphine Derivatives / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects*
D000701:Analgesics, Opioid; D002934:Cinnamates; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D009294:Narcotics; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C076806:clocinnamox; C081949:14-methoxymetopon; D009020:Morphine