Identification of opioid ligands possessing mixed μ agonist/δ antagonist activity among pyridomorphinans derived from naloxone, oxymorphone, and hydropmorphone

A series of pyridomorphinans derived from naloxone, oxymorphone, and hydromorphone (7a-k) were synthesized and evaluated for binding affinity at the opioid delta, mu, and kappa receptors in brain membranes using radioligand binding assays and for functional activity in vitro using [S-35] GTP-gamma-S binding assays in brain tissues and bioassays using guinea pig ileum (GPI) and mouse vas deferens (MVD) smooth muscle preparations. The pyridine ring unsubstituted pyridomorphinans possessing the oxymorphone and hydromorphone framework displayed nearly equal binding affinity at the mu and delta receptors. Their affinities at the K site were nearly 10-fold less than their binding affinities at the mu and delta sites. Introduction of aryl substituents at the 5'-position on the pyridine ring improved the binding affinity at the delta site while decreasing the binding affinity at the mu site. Nearly all of the ligands possessing an N-methyl group at the 17-position with or without a hydroxyl group at the 14-position of the morphinan moiety displayed agonist activity at the u receptor with varying potencies and efficacies. In the [S-35] GTP-gamma-S binding assays, most of these pyridomorphinans were devoid of any significant agonist activity at the delta and kappa receptors but displayed moderate to potent antagonist activity at the delta receptors. In antinociceptive evaluations using the warm-water tall-withdrawal assay in mice, the pyridomorphinans produced analgesic effects with varying potencies and efficacies when administered by the intracerebroventricular route. Among the ligands studied, the hydromorphone-derived 4-chlorophenylpyridomorphinan 7h was identified as a ligand possessing a promising profile of mixed mu agonist/delta antagonist activity in vitro and in vivo. In a repeated administration paradigm in which the standard mu agonist morphine produces significant tolerance, repeated administration of the mu agonist/delta antagonist ligand 7h produced no tolerance. These results indicate that appropriate molecular manipulations of the morphinan templates could provide ligands with mixed mu agonist/delta antagonist profiles and such ligands may have the potential of emerging as novel analgesic drugs devoid of tolerance, dependence, and related side effects.