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
- 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...
- 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 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...