Sunday, May 5, 2024
5/5/2024
Project Summary/Abstract Drug-use and addiction are complex social and medical issues and many strategies are being employed to decrease the detrimental effects of opioid addiction. The United States is in the midst of an opioid epidemic. The first-line treatment for opioid overdose is the opioid antagonist, naloxone, which competes for binding to the orthosteric site of µ-opioid receptors (MOR). Unfortunately, naloxone exhibits decreased effectiveness in cases of overdose involving potent synthetic opioids, often requiring repeated administration. This study seeks to identify novel counter-measures for synthetic opioids, with an emphasis on fentanyl. This project will identify novel agents which reverse the effects of fentanyl. We will utilize larval zebrafish as an in vivo high-throughput competitive environment to measure the ability of substances to counter-act the effects of synthetic opioids. The zebrafish paradigm also models drug uptake and biodistribution, which are recognized as being important contributors to the clinical interactions between opioids and naloxone. Commercially available screening libraries will be filtered to define a library of thousands of compounds with physiochemical properties which forecast CNS drug-likeness. In Aim 1, this library will be procured and tested for ability to reverse the effects of fentanyl in a novel photomotor response (PMR) assay we have developed. Preliminary data within the application provides high confidence that we will be able to use this PMR assay to successfully identify novel chemical classes which work via conventional competitive orthosteric inhibition of the MOR to reverse the effects of synthetic opioids. This is a likely outcome which is valuable in its own right and relatively low risk. The high-risk/high-reward prospect of this work is the potential identification of novel chemical classes which work via non-MOR mechanisms to reverse overdose from synthetic opioids. This is a unique advantage of the PMR phenotypic screen, which provides the opportunity to identify agents working via non-MOR mechanism- an outcome which target-based approaches cannot provide. Hit compounds capable of reversing the effects of fentanyl in an equivalent, or improved, fashion relative to naloxone will be studied in a follow-up confirmatory assay (Aim 2) focusing on ability to rescue fentanyl induced depression of cardiovascular function in zebrafish. Upon completion, this screening campaign will deliver novel small molecules capable of reversing the effects of synthetic opioids. Such molecules are anticipated to work as: 1) novel MOR allosteric modulators, 2) novel MOR orthosteric antagonists, and/or 3) novel agents acting via a non-MOR mechanism. Successful compounds will have favorable physiochemical properties as potential CNS agents and have demonstrated in vivo efficacy, which presumably dictates adequate CNS exposure and BBB penetration. As such, the ‘hits’ delivered from this project will serve as excellent starting points for future hit-to-lead optimization campaigns.
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