LONG-ACTING OPIATE ANTAGONISTS

Summary

Principal Investigator: PHILIP PORTOGHESE
Affiliation: University of Minnesota
Country: USA
Abstract: The development of long-acting opioid antagonists which selectively form divalent bonds with opioid receptors will be continued. Naltrexone,a potent narcotic antagonist, will be modified at the C-6 position with reactive groups. The groups will be attached to the 6 alpha or 6 beta position and varied in length in an effort to obtain ligands which possess maximum selectivity and efficiency in the covalent binding to opioid receptors. Oxymorphone, a potent agonist that is closely related to naltrexone, will be converted to target compound containing C-6 substituents that are identical to those in the antagonist series. All target compounds will be tested for agonist and antagonist effects in mice, guinea pig ileum, and rat-brain tissue. The narcotic antagonists will also be elaluated for their ability to inhibit opiate dependence in mice. Protection studies will be carried out to determine the specificity of the effects in vivo and in vitro. The antagonist and agonist target compounds that are most selective will be prepared in radiolabeled form for inital sudies directed toward the characterization of opioid receptors.
Funding Period: 1976-06-29 - 1981-05-31
more information: NIH RePORT

Top Publications

  1. pmc Clinically employed opioid analgesics produce antinociception via μ-δ opioid receptor heteromers in Rhesus monkeys
    Ajay S Yekkirala
    Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, Minnesota 55455, United States Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA
    ACS Chem Neurosci 3:720-7. 2012
  2. pmc The δ opioid receptor agonist SNC80 selectively activates heteromeric μ-δ opioid receptors
    Matthew D Metcalf
    Department of Medicinal Chemistry, University of Minnesota College of Pharmacy, Minneapolis, Minnesota, USA
    ACS Chem Neurosci 3:505-9. 2012
  3. pmc Standard opioid agonists activate heteromeric opioid receptors: evidence for morphine and [d-Ala(2)-MePhe(4)-Glyol(5)]enkephalin as selective μ-δ agonists
    Ajay S Yekkirala
    Department of Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA
    ACS Chem Neurosci 1:146-54. 2010
  4. pmc Opioid activity of spinally selective analogues of N-naphthoyl-β-naltrexamine in HEK-293 cells and mice
    Morgan Le Naour
    Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States
    J Med Chem 55:670-7. 2012
  5. pmc Allosteric interactions between δ and κ opioid receptors in peripheral sensory neurons
    Kelly A Berg
    Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229, USA
    Mol Pharmacol 81:264-72. 2012
  6. pmc N-naphthoyl-beta-naltrexamine (NNTA), a highly selective and potent activator of μ/kappa-opioid heteromers
    Ajay S Yekkirala
    Department of Medicinal Chemistry, College of Pharmacy, Medical School, University of Minnesota, Minneapolis, MN 55455, USA
    Proc Natl Acad Sci U S A 108:5098-103. 2011
  7. doi Consequences of opioid receptor mutation on actions of univalent and bivalent kappa and delta ligands
    Michael A Ansonoff
    Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA
    Psychopharmacology (Berl) 210:161-8. 2010
  8. pmc Modulation of cell surface expression of nonactivated cholecystokinin receptors using bivalent ligand-induced internalization
    Kaleeckal G Harikumar
    Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, Arizona 85259, USA
    J Med Chem 53:2836-42. 2010
  9. doi A bivalent ligand (KMN-21) antagonist for mu/kappa heterodimeric opioid receptors
    Shijun Zhang
    Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
    Bioorg Med Chem Lett 19:6978-80. 2009
  10. pmc Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial
    George E Woody
    Department of Psychiatry, Treatment Research Institute, University of Pennsylvania, 150 S Independence Mall W, Ste 600, Philadelphia, PA 19106, USA
    JAMA 300:2003-11. 2008

Scientific Experts

  • K A Berg
  • GEORGE EDWARD WOODY
  • Philip S Portoghese
  • Ajay S Yekkirala
  • Mary M Lunzer
  • Matthew D Metcalf
  • Morgan Le Naour
  • Michael D Powers
  • Alexander E Kalyuzhny
  • Michael A Ansonoff
  • Kaleeckal G Harikumar
  • Shijun Zhang
  • Maria Waldhoer
  • Matthew L Banks
  • George L Wilcox
  • Carolyn A Fairbanks
  • Kenner C Rice
  • Mike D Powers
  • Stevens S Negus
  • Kelley F Kitto
  • Sandra C Roerig
  • Christopher R McCurdy
  • Laurence J Miller
  • Eyup Akgün
  • John E Pintar
  • Ajay Yekkirala
  • Ye Tang
  • Robert M Jones
  • Jennifer L Whistler
  • Jamie Fong
  • Shiv K Sharma
  • Evi Kostenis

Detail Information

Publications11

  1. pmc Clinically employed opioid analgesics produce antinociception via μ-δ opioid receptor heteromers in Rhesus monkeys
    Ajay S Yekkirala
    Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, Minnesota 55455, United States Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA
    ACS Chem Neurosci 3:720-7. 2012
    ..These results open the door for further investigation in humans...
  2. pmc The δ opioid receptor agonist SNC80 selectively activates heteromeric μ-δ opioid receptors
    Matthew D Metcalf
    Department of Medicinal Chemistry, University of Minnesota College of Pharmacy, Minneapolis, Minnesota, USA
    ACS Chem Neurosci 3:505-9. 2012
    ..Thus, the data suggest that heteromeric μ-δ receptors should be considered as a target when SNC80 is employed as a pharmacological tool in vivo...
  3. pmc Standard opioid agonists activate heteromeric opioid receptors: evidence for morphine and [d-Ala(2)-MePhe(4)-Glyol(5)]enkephalin as selective μ-δ agonists
    Ajay S Yekkirala
    Department of Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA
    ACS Chem Neurosci 1:146-54. 2010
    ..The far-reaching implications of these results are discussed...
  4. pmc Opioid activity of spinally selective analogues of N-naphthoyl-β-naltrexamine in HEK-293 cells and mice
    Morgan Le Naour
    Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States
    J Med Chem 55:670-7. 2012
    ..The in vivo studies reveal that many of the ligands are more potent spinally than supraspinally and devoid of tolerance...
  5. pmc Allosteric interactions between δ and κ opioid receptors in peripheral sensory neurons
    Kelly A Berg
    Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229, USA
    Mol Pharmacol 81:264-72. 2012
    ....
  6. pmc N-naphthoyl-beta-naltrexamine (NNTA), a highly selective and potent activator of μ/kappa-opioid heteromers
    Ajay S Yekkirala
    Department of Medicinal Chemistry, College of Pharmacy, Medical School, University of Minnesota, Minneapolis, MN 55455, USA
    Proc Natl Acad Sci U S A 108:5098-103. 2011
    ....
  7. doi Consequences of opioid receptor mutation on actions of univalent and bivalent kappa and delta ligands
    Michael A Ansonoff
    Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA
    Psychopharmacology (Berl) 210:161-8. 2010
    ..More recent studies have begun to investigate whether heterodimer formation also occurs in vivo...
  8. pmc Modulation of cell surface expression of nonactivated cholecystokinin receptors using bivalent ligand-induced internalization
    Kaleeckal G Harikumar
    Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, Arizona 85259, USA
    J Med Chem 53:2836-42. 2010
    ..Receptor tethering with appropriate bivalent ligands can down-regulate signaling by moving a nonactivated receptor into the endocytic pathway...
  9. doi A bivalent ligand (KMN-21) antagonist for mu/kappa heterodimeric opioid receptors
    Shijun Zhang
    Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
    Bioorg Med Chem Lett 19:6978-80. 2009
    ..Evaluation of the series in HEK-293 cells revealed 4 (KMN-21) to selectively antagonize the activation of kappa-mu heterodimers, suggesting possible bridging of receptors when the bivalent ligand spacer contains 21 atoms...
  10. pmc Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial
    George E Woody
    Department of Psychiatry, Treatment Research Institute, University of Pennsylvania, 150 S Independence Mall W, Ste 600, Philadelphia, PA 19106, USA
    JAMA 300:2003-11. 2008
    ..The usual treatment for opioid-addicted youth is detoxification and counseling. Extended medication-assisted therapy may be more helpful...
  11. pmc A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers
    Maria Waldhoer
    Ernest Gallo Clinic and Research Center, University of California, San Francisco, CA 94608, USA
    Proc Natl Acad Sci U S A 102:9050-5. 2005
    ..Importantly, targeting opioid heterodimers could provide an approach toward the design of analgesic drugs with reduced side effects...