Browsing by Author "Husbands, Stephen M."

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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
(ACS Publications, 2015) Cueva, Juan Pablo; Roche, Christopher; Ostovar, Mehrnoosh; Kumar, Vinod; Clark, Mary J.; Hillhouse, Todd M.; Lewis, John W.; Traynor, John R.; Husbands, Stephen M.
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.
Pyrrolo- and pyridomorphinans: Non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists
(Elsevier, 2014) Kumar, Vinod; Clark, Mary J.; Traynor, J. R.; Lewis, J. W.; Husbands, Stephen M.
Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse.
Selectively Promiscuous Opioid Ligands: Discovery of High Affinity/ Low Efficacy Opioid Ligands with Substantial Nociceptin Opioid Peptide Receptor Affinity
(ACS Publications, 2014) kumar, Vinod; Ridzwan, Irna E.; Grivas, Konstantinos; Lewis, John W.; Clark, Mary J.; Meurice, Claire; Jimenez-Gomez, Corina; Pogozheva, Irina; Mosberg, Henry; Traynor, John R.; Husbands, Stephen M.
Emerging clinical and preclinical evidence suggests that a compound displaying high affinity for μ, κ, and δ opioid (MOP, KOP, and DOP) receptors and antagonist activity at each, coupled with moderate affinity and efficacy at nociceptin opioid peptide (NOP) receptors will have utility as a relapse prevention agent for multiple types of drug abuse. Members of the orvinol family of opioid ligands have the desired affinity profile but have typically displayed substantial efficacy at MOP and or KOP receptors. In this study it is shown that a phenyl ring analogue (1d) of buprenorphine displays the desired profile in vitro with high, nonselective affinity for the MOP, KOP, and DOP receptors coupled with moderate affinity for NOP receptors. In vivo, 1d lacked any opioid agonist activity and was an antagonist of both the MOP receptor agonist morphine and the KOP receptor agonist ethylketocyclazocine, confirming the desired opioid receptor profile in vivo.