Selective Opioid Ligands

Summary

Principal Investigator: PHILIP PORTOGHESE
Affiliation: University of Minnesota
Country: USA
Abstract: Given the potential pharmacological and physiological diversity arising from heterodimerization of opioid receptors, an important challenge in opioid research is the development of selective tools for the investigation of such phenotypic opioid receptors. Selective pharmacological tools that can span the divide between cultured cells and in vivo systems would clarify the functional roles and localization of heterodimeric opioid receptors in experimental animals. Thus, the broad, long-term objectives of this research are to develop ligands with selectivity for heterodimeric opioid receptors as tools to study the functional roles of physically associated opioid receptors in the central nervous system. The long-term goal is to use the information obtained from such studies to develop superior analgesics that are devoid of tolerance and dependence. The specific aims of the present application include the synthesis and biological evaluation of ligands that are selective for opioid receptor heterodimers. Based on reports of heterodimeric opioid receptors in cultured cells and on the large body of literature that implicates interaction between mu and kappa opioid receptors and mu and NK1, CCK2, ORL1, and CB1 receptors in vivo, a total of ten series of compounds will be synthesized. Eight of the proposed series are bivalent ligands that will include mu and kappa opioid pharmacophores or a mu agonist pharmacophore combined with NK1, CCK2, ORL1, or CB1 antagonist pharmacophores. The pharmacophores in each of these bivalent series will be linked to each other through spacers containing 12-22 atoms. The antagonist non-opioid pharmacophores were selected because interaction between mu opioid receptors and the above receptors have been reported to modulate antinociception, tolerance and/or dependence. The corresponding series of monovalent ligands with matching spacers and matching pharmacophores will be synthesized as controls. There will be 11 compounds in each of these 16 series. The remaining two series will be structurally related to 6'-GNTI which has been reported to produce analgesia in mice by selectively targeting spinal delta-kappa opioid receptor heterodimers. Because analgesia of 6'-GNTI is mediated spinally, such compounds should not possess the supraspinal side-effects generally associated with clinically employed analgesics. As a second approach to development of spinally-selective analgesics, the Pl/s library of ~1000 opiates will undergo Flexstation screening on cultured cells containing coexpressed and singly expressed delta and kappa opioid receptors. Target compounds and screening hits will be tested in cultured cells and in behavioral tests in mice that include evaluation of tolerance and physical dependence.
Funding Period: 1981-06-01 - 2012-05-31
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
  • Morgan Le Naour
  • Matthew D Metcalf
  • Michael D Powers
  • Alexander E Kalyuzhny
  • Kaleeckal G Harikumar
  • Michael A Ansonoff
  • Shijun Zhang
  • Maria Waldhoer
  • George L Wilcox
  • Mike D Powers
  • Kelley F Kitto
  • Matthew L Banks
  • Kenner C Rice
  • Carolyn A Fairbanks
  • Stevens S Negus
  • Sandra C Roerig
  • Christopher R McCurdy
  • Eyup Akgün
  • John E Pintar
  • Laurence J Miller
  • Ajay Yekkirala
  • Ye Tang
  • Evi Kostenis
  • Robert M Jones
  • Jennifer L Whistler
  • Shiv K Sharma
  • Jamie Fong

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...