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
| Autor: | Juan Pablo Cueva, Mary J. Clark, John W. Lewis, Vinod Kumar, Stephen M. Husbands, Christopher Roche, John R. Traynor, Todd M. Hillhouse, Mehrnoosh Ostovar |
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| Rok vydání: | 2015 |
| Předmět: |
medicine.drug_class
Narcotic Antagonists Analgesic NOP Drug Evaluation Preclinical Receptors Opioid mu Chemistry Techniques Synthetic Pharmacology Ligands Partial agonist Nociceptin Receptor Article Structure-Activity Relationship SDG 3 - Good Health and Well-being Drug Discovery medicine Humans Chemistry Receptors Opioid kappa 3. Good health Buprenorphine Molecular Docking Simulation Nociceptin receptor Opioid Receptors Opioid Molecular Medicine μ-opioid receptor Opioid antagonist medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry Cueva, J P, Roche, C, Ostovar, M, Kumar, V, Clark, M J, Hillhouse, T M, Lewis, J W, Traynor, J R & Husbands, S M 2015, ' 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 ', Journal of Medicinal Chemistry, vol. 58, no. 10, pp. 4242-4249 . https://doi.org/10.1021/acs.jmedchem.5b00130 |
| ISSN: | 1520-4804 |
| DOI: | 10.1021/acs.jmedchem.5b00130 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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