Identification of Opioid Ligands Possessing Mixed μ Agonist/δ Antagonist Activity among Pyridomorphinans Derived from Naloxone, Oxymorphone, and Hydropmorphone

Subramaniam Ananthan, Naveen K. Khare, Surendra K. Saini, Lainne E. Seitz, Jeffrey L. Bartlett, Peg Davis, Christina M. Dersch, Frank Porreca, Richard B. Rothman, Edward J. Bilsky

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


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 the 17-position with or without a hydroxyl group at the 14-position of the morphinan moiety displayed 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 significant agonist activity at the δ and κ receptors but displayed moderate to potent antagonist activity at the δ receptors. In antinociceptive evaluations using the warm-water tail-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 μ agonist/δ antagonist activity in vitro and in vivo. In a repeated administration paradigm in which the standard μ agonist morphine produces significant tolerance, repeated administration of the μ agonist/δ antagonist ligand 7h produced no tolerance. These results indicate that appropriate molecular manipulations of the morphinan templates could provide ligands with mixed μ agonist/δ antagonist profiles and such ligands may have the potential of emerging as novel analgesic drugs devoid of tolerance, dependence, and related side effects.

Original languageEnglish (US)
Pages (from-to)1400-1412
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number6
StatePublished - Mar 11 2004

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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