Novel ligands for the opioid receptors: Synthesis and structure-activity relationships among 5′-aryl and 5′-heteroaryl 17-cyclopropylmethyl-4,5α-epoxypyrido[2′,3′:6,7]morphinans

Subramaniam Ananthan, Naveen K. Khare, Surendra K. Saini, Peg Davis, Christina M. Dersch, Frank Porreca, Richard B. Rothman

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

A series of pyridomorphinans possessing an aryl (10a-s) or heteroaryl (11a-h) substituent at the 5′-position of the pyridine ring of 17-cyclopropylmethyl-4,5α-epoxypyrido[2′,3′:6,7]morphinan was synthesized and evaluated for binding and functional activity at the opioid δ, μ, and κ receptors. All of these pyridomorphinans bound with higher affinity at the δ site than at μ or κ sites. The binding data on isomeric compounds revealed that there exists greater bulk tolerance for substituents placed at the o-position of the phenyl ring than at m- or p-positions. Among the ligands examined, the 2-chlorophenyl (10l), 2-nitrophenyl (10n), 2-pyridyl (11a), and 4-quinolinyl (11g) compounds bound to the δ receptor with subnanomolar affinity. Compound 10c with the p-tolyl substituent displayed the highest μδ selectivity (ratio=42) whereas compound 10l with the 2-chlorophenyl substituent displayed the highest κδ selectivity (ratio=23). At 10 μM concentration, the in vitro functional activity determined using [35S]GTP-γ-S binding assays showed that all of the compounds were antagonists devoid of any significant agonist activity at the δ, μ, and κ receptors. Antagonist potency determinations of three selected ligands revealed that the p-tolyl compound 10c is a potent δ selective antagonist. In the [ 35S]GTP-γ-S assays this compound had a functional antagonist Ki value of 0.2, 4.52, and 7.62 nM at the δ, μ, and κ receptors, respectively. In the smooth muscle assays 10c displayed δ antagonist potency with a Ke value of 0.88 nM. As an antagonist, it was 70-fold more potent at the δ receptors in the MVD than at the μ receptors in the GPI. The in vitro δ antagonist profile of this pyridomorphinan 10c resembles that of the widely used δ selective antagonist ligand naltrindole.

Original languageEnglish (US)
Pages (from-to)4143-4154
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number18
DOIs
StatePublished - Sep 1 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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