Abstract
Abstract
DISCOVERY OF MOR SELECTIVE, REVERSIBLE OPIOID ANTAGONIST FOR POTENTIAL USE IN TREATMENT OF DRUG DEPENDENCE
Abdulmajeed M. Jali, M.S.
A thesis submitted in partial fulfillment of the requirements of Master of Science at Virginia Commonwealth University.
Virginia Commonwealth University, 2017
Director: Dana E. Selley, Ph. D., Department of Pharmacology and Toxicology
Opioid dependence/addiction is a major public health problem that is associated with multiple health and social costs. Pharmacotherapeutic treatment has been relatively effective, but the risk of relapse after treatment remains high. Naltrexone, an opioid antagonist, is FDA-approved for long-term maintenance therapy to reduce relapse risk. However, naltrexone is accompanied by side-effects that are due to lack of selectivity among opioid receptor types. Based on the message-address concept and molecular modeling studies, 18 novel compounds designed to bind selectively to the MOR based on interaction with a key aromatic residue, were synthesized by our collaborators. The purpose of this study was to identify MOR-selective antagonists from this series of compounds. Using radioligand and GTPgS binding assays in transfected cells and native tissues, two compounds were discovered with the high MOR-selectivity and low efficacy required to serves as lead ligands in future discovery efforts toward next-generation opioid antagonists.