LONG-ACTING OPIATE ANTAGONISTS
Principal Investigator: PHILIP PORTOGHESE
Affiliation: University of Minnesota
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
- 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...