| Abstract
| - A series of pyridomorphinans derived from naloxone, oxymorphone, and hydromorphone (7a−k) were synthesized and evaluated for binding affinity at the opioid δ, μ, and κ receptors inbrain membranes using radioligand binding assays and for functional activity in vitro using[35S]GTP-γ-S binding assays in brain tissues and bioassays using guinea pig ileum (GPI) andmouse vas deferens (MVD) smooth muscle preparations. The pyridine ring unsubstitutedpyridomorphinans possessing the oxymorphone and hydromorphone framework displayednearly equal binding affinity at the μ and δ receptors. Their affinities at the κ site were nearly10-fold less than their binding affinities at the μ and δ sites. Introduction of aryl substituentsat the 5‘-position on the pyridine ring improved the binding affinity at the δ site while decreasingthe binding affinity at the μ site. Nearly all of the ligands possessing an N-methyl group atthe17-position with or without a hydroxyl group at the 14-position of the morphinan moietydisplayed agonist activity at the μ receptor with varying potencies and efficacies. In the[35S]GTP-γ-S binding assays, most of these pyridomorphinans were devoid of any significantagonist activity at the δ and κ receptors but displayed moderate to potent antagonist activityat the δ receptors. In antinociceptive evaluations using the warm-water tail-withdrawal assayin mice, the pyridomorphinans produced analgesic effects with varying potencies and efficacieswhen administered by the intracerebroventricular route. Among the ligands studied, thehydromorphone-derived 4-chlorophenylpyridomorphinan 7h was identified as a ligand possessing a promising profile of mixed μ agonist/δ antagonist activity in vitro and in vivo. In arepeated administration paradigm in which the standard μ agonist morphine producessignificant tolerance, repeated administration of the μ agonist/δ antagonist ligand 7h producedno tolerance. These results indicate that appropriate molecular manipulations of the morphinantemplates could provide ligands with mixed μ agonist/δ antagonist profiles and such ligandsmay have the potential of emerging as novel analgesic drugs devoid of tolerance, dependence,and related side effects.
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