C7β-Methyl Analogues of the Orvinols: The Discovery of Kappa Opioid Antagonists with Nociceptin/Orphanin FQ Peptide (NOP) Receptor Partial Agonism and Low, or Zero, Efficacy at Mu Opioid Receptors

Juan Pablo Cueva, Christopher Roche, Mehrnoosh Ostovar, Vinod Kumar, Mary J. Clark, Todd M. Hillhouse, John W. Lewis, John R. Traynor, Stephen M. Husbands

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)
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Abstract

Buprenorphine is a successful analgesic and treatment for opioid abuse, with both activities relying on its partial agonist activity at mu opioid receptors. However, there is substantial interest in its activities at the kappa opioid and nociceptin/orphanin FQ peptide receptors. This has led to an interest in developing compounds with a buprenorphine-like pharmacological profile but with lower efficacy at mu opioid receptors. The present article describes aryl ring analogues of buprenorphine in which the standard C20-methyl group has been moved to the C7β position, resulting in ligands with the desired profile. In particular, moving the methyl group has resulted in far more robust kappa opioid antagonist activity than seen in the standard orvinol series. Of the compounds synthesized, a number, including 15a, have a profile of interest for the development of drug abuse relapse prevention therapies or antidepressants and others (e.g., 8c), as analgesics with a reduced side-effect profile.

Original languageEnglish
Pages (from-to)4242-4249
Number of pages8
JournalJournal of Medicinal Chemistry
Volume58
Issue number10
Early online date6 May 2015
DOIs
Publication statusPublished - 28 May 2015

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