Abstract
5β-Methyl-7,8-dihydromorphinone (metopon), an isomer [6a S-(6aα,9aα,10β)13a S]-1,10-methano-4-hydroxy-11-methyl 6,6a,8,9,10,11,12,13-octahydro-[1]-benzopyrano[4,3,e]isoquinoline-7-(9a H)-one (compound 1) derived from a photochemical rearrangement of 5β-methylmorphinone, and [6a S-(6aα,9aα,10β)13a S]-1,10-methano-4-hydroxy-11-methyl-6,6a,8,9, 10,11,12,13-octahydro-[1]-benzopyrano[4,3,e]-14β-( p-nitrocinnamoylamino) isoquinoline-7-(9a H)-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-Ala 2,(Me)-Phe 4,Gly(ol) 5]enkephalin (DAMGO), a μ-selective peptide, with IC 50 values less than 5 nM. All three compounds exhibited lower affinity for δ- and κ-opioid receptors. In the mouse 55 °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 μ-selective, irreversible opioid receptor antagonist β-funaItrexamine blocked antinociception induced by metopon and compound 1, while δ- and κ-opioid receptor selective antagonists did not effect antinociception. These findings demonstrate metopon and its isomer bound with high affinity to the μ-opioid receptor and produced antinociception through this receptor.
Published Version
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