Opioid activity of spinally selective analogues of N -naphthoyl-β- naltrexamine in HEK-293 cells and mice

Morgan Le Naour, Mary M. Lunzer, Mike D. Powers, Philip S. Portoghese

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Using the selective mu-kappa agonist, N-naphthoyl-β-naltrexamine 1, as the prototype ligand, a series of closely related naphthalene analogues were synthesized to study the chemical space around the naphthalene moiety in an effort to evaluate how receptor selectivity is affected by chemical modification. Nine analogues (2-10) of compound 1 were synthesized and tested on HEK-293 cells expressing homomeric and heteromeric opioid receptors, and in the mouse tail-flick assay. It was found that a small change in structure produces profound changes in selectivity in this series. This is exemplified by the discovery that introduction of a 6-fluoro group transforms 1 from a selective mu-kappa heteromeric receptor agonist to a delta-preferring agonist 7. The in vivo studies reveal that many of the ligands are more potent spinally than supraspinally and devoid of tolerance.

Original languageEnglish (US)
Pages (from-to)670-677
Number of pages8
JournalJournal of medicinal chemistry
Volume55
Issue number2
DOIs
StatePublished - Jan 26 2012

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