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 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
  2. 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
  3. 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

Scientific Experts

  • GEORGE EDWARD WOODY
  • Shijun Zhang
  • Philip S Portoghese
  • Maria Waldhoer
  • Ye Tang
  • Ajay Yekkirala
  • Jennifer L Whistler
  • Jamie Fong
  • Shiv K Sharma
  • Mary M Lunzer
  • Evi Kostenis
  • Robert M Jones

Detail Information

Publications3

  1. 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...
  2. 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...
  3. 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...