Mamoun, AlhamadshehBalgoname, Abdulmalek Ahmed2024-12-262024Balgoname, A. A. (2024). Design and synthesis of rapid-release naloxone ester conjugates for enhanced antidote efficacy (Order No. 31767352). Available from Dissertations & Theses @ University of the Pacific; ProQuest Dissertations & Theses Global. (3148381540). Retrieved from https://pacificatclassic.pacific.edu/wamvalidate?url=https://www.proquest.com/dissertations-theses/design-synthesis-rapid-release-naloxone-ester/docview/3148381540/se-29798346873891https://hdl.handle.net/20.500.14154/74442Abstract By Abdulmalek Ahmed Balgoname University of the Pacific 2024 The opioid crisis remains a major public health challenge, exacerbated by the surge in overdose deaths linked to potent synthetic opioids such as fentanyl. Naloxone, a life-saving opioid antagonist, is pivotal in emergency overdose interventions due to its rapid reversal of opioid effects. However, its short duration of action limits its effectiveness, particularly in situations where timely medical follow-up is unavailable. To address this limitation, our lab has developed an innovative prodrug delivery system for naloxone, aimed at enhancing its pharmacokinetic profile and enabling controlled, sustained release. This dissertation research focuses on the synthesis and in vitro stability evaluation of novel naloxone ester conjugates. The study highlights the influence of ester chemistry, where variations in the steric and electronic properties of the ester moiety significantly impact hydrolysis rates and naloxone release in plasma. Steric hindrance near the ester bond modulates access to hydrolytic enzymes, while electronic effects govern bond polarization, collectively fine-tuning the release profile. These findings underline the potential of tailored ester chemistry to optimize naloxone delivery and address the challenges of opioid overdose management, paving the way for improved patient outcomes.127en-USProdrugOpioid overdoseNaloxone ester conjugatesAntidoteThesis