Novel fentanyl derivatives as counteracting agents against fentanyl

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Project Summary This proposal is in response to the Notice of Special Interest (NOT-NS-20-030): Administrative Supplements to Promote and Expand into the Research and Development of Medical Countermeasures Against Chemical Threats. We plan to pursue the development of novel and potent fentanyl derivatives as mu opioid receptor (MOR) modulators to counteract the acute exposure to potent synthetic opioid threat, i.e. fentanyl and its analogs. The fentanyls are a large family of synthetic opioids and are prominent on the list of potential chemical threats. The fact that some of them are up to 10,000-fold more potent than morphine and they can be aerosolized or placed into food/water makes the potential of a chemical attack using them becoming real. Designer fentanyls can be synthesized at a single location and are readily available on the street. Because of their high potency and longer half-life than naloxone, the front-line treatment for fentanyl overdose, multiple infusions and high doses of naloxone may be required during reversal procedure. Emergency responders often have a limited supply of naloxone, which could easily be depleted. All these may lead to higher fatality rate if a large population is under attack. Recently we have identified a novel molecular mechanism of fentanyl binding and activation on its target protein, the MOR, through systematic computational chemistry studies. Accordingly, we plan to apply these molecular modeling findings to design novel MOR modulators based on the structural skeleton of phenylfentanil, a neutral antagonist on the MOR, and to study their potential to specifically reverse the function of fentanyl and its analogs on the MOR more effectively and specifically. Following the completion of this pilot project, we plan to establish a dynamic and continuous drug discovery and development pipeline to combat the acute toxicity of the opioid threat.