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 δ, μ, and κ receptors in brain 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) 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 μ and δ receptors. Their affinities at the κ site were nearly 10-fold less than their binding affinities at the μ and δ sites. Introduction of aryl substituents at the 5‘-position on the pyridine ring improved the binding affinity at the δ site while decreasing the binding affinity at the μ site. Nearly all of the ligands possessing an N-methyl group at the17-position with or without a hydroxyl group at the 14-position of the morphinan moiety disp...