iPSC-derived human neurons and OUD medications development

This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction. Today, a national epidemic of opioid drug poisoning deaths that began in the 1990s continues unabated. Fentanyl has become a popular street drug through its ability to induce a quick heroin-like euphoria. But fentanyl is a dangerous drug due to fentanyl-induced respiratory depression. Despite a medical need to alleviate pain, there is a need for a safe, long-lived, potent compound to combat abused fentanyl. We hypothesize that safe, small molecule ChemRegen Lead compounds will meet this critical unmet medical need. The over-arching goal of our proposed work is to design, synthesize and test non-opioid drug candidates and validate a molecular target that utilizes a well-established mechanism of action. The target is not an opioid receptor. Targeting a non-opioid receptor may help get a drug candidate into the clinic quicker. Phase I goals will be completed by addressing two Specific Aims including: Aim 1. Design and synthesize Leads and control compounds and characterize them chemically and pharmacologically for receptor binding. Do ADMET work on Leads. Aim 2. Characterize human induced pluripotent stem cell (hiPSC)-derived neurons from normal individuals for response to Leads, fentanyl and other opioids. In practice, Aims 1 and 2 will take place concurrently. Completion of the work will establish the importance of the approach in characterizing effects of opioids on human neurons of normal subjects. Future work will involve neuronal cells from other cohorts. The work will validate a molecular target for drug development and do “drug development in a dish”. The significance of the work is that fundamental cellular, biochemical and drug development information will result in a new approach to identify Leads to reverse effects of synthetic opioids and spur further pre-clinical development. Overall, the information will lead to a clearer understanding of a new way to combat opioid-induced respiratory depression and advance our understanding of new, safe drug candidates to reverse fentanyl toxicity.