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J Med Chem. 2015 May 28;58(10):4242-9. doi: 10.1021/acs.jmedchem.5b00130. Epub 2015 May 6.

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.

Author information

1
†Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, United Kingdom.
2
‡Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.

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.

PMID:
25898137
PMCID:
PMC4450370
DOI:
10.1021/acs.jmedchem.5b00130
[Indexed for MEDLINE]
Free PMC Article

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