14-Methoxymetopon, a very potent mu-opioid receptor-selective analgesic with an unusual pharmacological profile.

14-Methoxymetopon is a potent opioid analgesic. When given systemically, it is approximately 500-fold more active than morphine. However, this enhanced potency is markedly increased with either spinal or supraspinal administration, where its analgesic activity is more than a million-fold greater than morphine. It was mu-opioid receptor selective in binding assays and its analgesia was blocked only by mu-opioid receptor-selective antagonists. Yet, it had a different selectivity profile than either morphine or morphine-6beta-glucuronide. Unlike morphine, 14-methoxymetopon was antagonized by 3-O-methylnaltrexone, it was sensitive to antisense probes targeting exons 1, 2 and 8 of the opioid receptor gene and was inactive both spinally and supraspinally in CXBK mice. Although it retarded gastrointestinal transit, it displayed a ceiling effect with no dose lowering transit by more than 65%, in contrast to the complete inhibition of transit by morphine. These finding demonstrate that 14-methoxymetopon is a highly potent mu-opioid with a pharmacological profile distinct from that of the traditional mu-opioid morphine.