title: 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.
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.
authors.affiliation: †Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, United Kingdom.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Cueva
authors.affiliation: †Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Roche
authors.affiliation: †Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, United Kingdom.
authors.forename: Mehrnoosh
authors.initials: M
authors.lastname: Ostovar
authors.affiliation: †Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, United Kingdom.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: ‡Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Clark
authors.affiliation: ‡Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Hillhouse
authors.affiliation: †Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, United Kingdom.
authors.forename: John W
authors.initials: JW
authors.lastname: Lewis
authors.affiliation: ‡Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
authors.affiliation: †Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, United Kingdom.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Husbands
mesh_terms: D002047:Buprenorphine / Q000031:analogs & derivatives; D060326:Chemistry Techniques, Synthetic; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D009292:Narcotic Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000819:agonists*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
chemical_list: D008024:Ligands; D009292:Narcotic Antagonists; C515653:OPRK1 protein, human; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D002047:Buprenorphine; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human