Grant: Project Grant

The most recent data available from the Public Health Agency of Canada shows that a total of 3,970 apparent opioid-toxicity deaths occurred between January to June 2023 - approximately 22 deaths per day. In the same timeframe, 20,758 Emergency Medical Service responses occurred due to suspected opioid-related overdoses. This is a major impact on Canadian society. Despite the risks, individuals who are dependent on opioids face major challenges in achieving opioid abstinence due to the intense withdrawal symptoms that often occur. By reducing the effects of withdrawal, one of the major barriers to overcoming opioid dependence would be removed. Our team has discovered that pannexin-1 (Panx1) is a key determinant of opioid withdrawal and blocking this channel produces a striking alleviation of withdrawal. Blocking Panx1 reduces the severity of withdrawal symptoms. As known inhibitors of Panx1 have moderate potency and penetration into the brain, there is an urgent need to develop improved drugs targeting Panx1 to create therapeutics that treat opioid withdrawal. Preliminary work from our team has developed lead Panx1 inhibitors with significantly improved potency and drug-like properties. This proposal identifies three complementary strategies to create Panx1 inhibitors. We will use the tools of structure-based and ligand-based drug design, and reversible covalent inhibitors to aid in the development of new therapeutics. This proposal brings together an outstanding team including scientists with expertise in medicinal chemistry, molecular simulations, neuroscience, and structural biology. As the global health crisis of opioid-related deaths continues to grow, there is an urgency to improve treatment options. Our team will advance the development of a non-opioid option for the treatment of opioid withdrawal to help individuals break the cycle of drug dependence.