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.
King
Michael A
MA
The Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Su
Wendy
W
Nielan
Claire L
CL
Chang
Albert H
AH
Schütz
Johannes
J
Schmidhammer
Helmut
H
Pasternak
Gavril W
GW
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009022:Morphine Derivatives / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000700:Analgesics; D009022:Morphine Derivatives; D017450:Receptors, Opioid, mu; C081949:14-methoxymetopon