SELECTIVE NON-PEPTIDE MU-OPIOID RECEPTOR ANTAGONIST: DESIGN, SYNTHESIS AND BIOLOGICAL STUDIES

Abstract

SELECTIVE NON-PEPTIDE MU-OPIOID RECEPTOR ANTAGONISTS: DESIGN, SYNTHESIS AND PHARMACOLOGICAL STUDIES By Lindsey C. K. Aschenbach, M.S. A thesis submitted in partial fulfillment of the requirements for the degree of Masters of Science at Virginia Commonwealth University. Virginia Commonwealth University, 2008 Major Director: Dr. Yan Zhang, Assistant Professor Department of Medicinal Chemistry There are currently many opioid agonists available for clinical use as analgesics. However, many of these opioid agonists have notorious side effects including respiratory depression and may lead to addiction and dependence. Problems associated with these opioid agonists are determined to come from their interactions with the mu-opioid receptor. Opioid antagonists, such as naltrexone, have shown to aid in the treatment of opioid addiction. Although naltrexone has high affinity to the mu-opioid receptor, it lacks selectivity. Novel selective mu-opioid receptor antagonists were designed based on the identification of important pharmacophore elements in several known mu-opioid receptor agonists and antagonists. These compounds were synthesized and in vitro biological assays were conducted to determine their affinity to