Thursday, January 2, 2025
1/2/2025
PROJECT SUMMARY. Over 1.25 million emergency department visits occur annually due to the abuse of illicit drugs and prescription opioids resulting in an estimated cost to the United States of $37 billion/year in healthcare costs and $271.5 billion/year overall when crime and lost productivity are included. The majority of these cases were due to cocaine (40%), heroin (21%), (meth)amphetamines (13%), and PCP (6%) with numbers rising in recent years for fentanyl, fentanyl analogues, and drugs (e.g. cocaine) laced with fentanyl. For this reason, the federal government considers the drug abuse (opioid) epidemic to be a national emergency. Currently, opioid overdose can be treated with Naloxone which binds to / blocks the opioid receptor in the brain. However, with the rising abuse of fentanyl, Naloxone is becoming much less effective and multiple doses are often required. Furthermore, there are no current specific antidotes for intoxication with stimulants (e.g. methamphetamine, cocaine, or mephedrone) or for hallucinogens (e.g. ketamine or PCP) and ER doctors deliver treatments that only target the patient’s symptoms. Accordingly, the development of new antidotes that treat intoxication with the full range of drugs of abuse (opioids, stimulants, hallucinogens) is urgently needed. In contrast to small molecule strategies that antagonize the opioid receptor, the molecular container strategy sequesters the drug itself in the bloodstream of the animal and promotes its clearance. Macrocyclic arenes are molecular container compounds that can possess tight binding (Ka ≥ 107 M-1; Kd ≤ 100 nM) toward hydrophobic cations in PBS which renders them a prime platform to create new in vivo sequestration agents for drugs of abuse. We propose to systematically vary the structure of the macrocyclic arene hosts to optimize the binding affinity toward specific drugs of abuse. For example, we will optimize the location of the anionic groups to maximize ion-ion electrostatic interactions and deepen / widen the macrocyclic arene cavity to enhance the hydrophobic driving force toward host•drug complexation. New sequestration agents will be subjected to a series of in vitro toxicology and in vivo maximum tolerated dose studies to establish their biocompatibility. Finally, hyperlocomotion assays will be used to determine the in vivo efficacy of the most promising sequestration agent / drug pairs. Upon completion of the proposed project we expect at least one sequestration agent will be nominated to continue toward US FDA investigational new drug status.
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