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, w e determined the efficacy (tau) and apparent in vivo affinity (K-A) Of the high-potency alkoxymorphinan 14-methoxymetopon. However, in the present stu dy, 14-methoxymetopon's efficacy proved to be only 1.5-fold higher than tha t of morphine (tau, 19 vs. 12). K-A values were 2,900 nmol/kg for 14-methox ymetopon and 46,000 nmol/kg for morphine (Ki for [H-3]DAMGO binding, 0.33 v s 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.