Metopon and two unique derivatives: affinity and selectivity for the multiple opioid receptors.
5 beta-Methyl-7,8-dihydromorphinone (metopon), an isomer [6aS-(6a alpha,9a alpha, 10 beta)13aS]-1,10-methano-4-hydroxy-11-methyl- 6,6a,8,9,10,11,12,13-octahydro-[1]-benzopyrano[4,3,e]isoquinoline- 7-(9aH)-one (compound 1) derived from a photochemical rearrangement of 5 beta-methylmorphinone, and [6aS-(6a alpha,9a alpha,10 beta)13aS]-1,10-methano-4-hydroxy-11-methyl- 6,6a,8,9, 10,11,12,13-octahydro-[1]-benzopyrano[4,3,e]-14 beta- (p-nitrocinnamoylamino) isoquinoline-7-(9aH)-one (compound 2) were characterized for opioid receptor affinity, selectivity and analgesic properties. In competition binding assays using bovine striatal membranes, the three compounds inhibited the binding of 0.25 nM [3H][D-Ala2,(Me)-Phe4,Gly(ol)5]enkephalin (DAMGO), a mu-selective peptide, with IC50 values less than 5 nM. All three compounds exhibited lower affinity for delta- and kappa-opioid receptors. In the mouse 55 degrees C warm-water tail-flick assay, both metopon and compound 1 displayed antinociception that lasted for 60 min after i.c.v. injection. Morphine sulfate, metopon and compound 1 produced 50% antinociception with i.c.v. doses of 0.83, 2.0 and 4.0 nmol, respectively. The mu-selective, irreversible opioid receptor antagonist beta-funaltrexamine blocked antinociception induced by metopon and compound 1, while delta- and kappa-opioid receptor selective antagonists did not effect antinociception. These findings demonstrate metopon and its isomer bound with high affinity to the mu-opioid receptor and produced antinociception through this receptor.
McLaughlin
J P
JP
Department of Pharmacology, University of Rochester, NY 14642, USA.
Nowak
D
D
Sebastian
A
A
Schultz
A G
AG
Archer
S
S
Bidlack
J M
JM
D000701:Analgesics, Opioid / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002417:Cattle; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009019:Morphinans / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D009020:Morphine / Q000493:pharmacokinetics / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism
D000701:Analgesics, Opioid; D009019:Morphinans; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009020:Morphine; C046877:metopon