Selective Opioid Ligands
Principal Investigator: PHILIP PORTOGHESE
Affiliation: University of Minnesota
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
- Clinically employed opioid analgesics produce antinociception via μ-δ opioid receptor heteromers in Rhesus monkeysAjay 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...
- The δ opioid receptor agonist SNC80 selectively activates heteromeric μ-δ opioid receptorsMatthew 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...
- Standard opioid agonists activate heteromeric opioid receptors: evidence for morphine and [d-Ala(2)-MePhe(4)-Glyol(5)]enkephalin as selective μ-δ agonistsAjay 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...
- Opioid activity of spinally selective analogues of N-naphthoyl-β-naltrexamine in HEK-293 cells and miceMorgan 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...
- Allosteric interactions between δ and κ opioid receptors in peripheral sensory neuronsKelly A Berg
Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229, USA
Mol Pharmacol 81:264-72. 2012....
- N-naphthoyl-beta-naltrexamine (NNTA), a highly selective and potent activator of μ/kappa-opioid heteromersAjay 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....
- Consequences of opioid receptor mutation on actions of univalent and bivalent kappa and delta ligandsMichael 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...
- Modulation of cell surface expression of nonactivated cholecystokinin receptors using bivalent ligand-induced internalizationKaleeckal 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...
- A bivalent ligand (KMN-21) antagonist for mu/kappa heterodimeric opioid receptorsShijun 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...
- Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trialGeorge 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...
- A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimersMaria 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...