clocinnamox and 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.

Topics: Analgesics, Opioid; Animals; Binding, Competitive; Cinnamates; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Hot Temperature; Male; Mice; Mice, Inbred C57BL; Morphine; Morphine Derivatives; Narcotic Antagonists; Narcotics; Pain Measurement; Receptors, Opioid, mu; Signal Transduction