Discovery of GPR171 small molecule ligands for the treatment of chronic pain

项目总结

Project Summary Chronic pain is a debilitating medical condition, affecting roughly 50 million people in the United States. Opioids are the common prescribed class of medicine for moderate to severe pain, but they are not particularly effective in treating many types of chronic pain. Opioids have potentially fatal side effect of respiratory depression, and long-term opioid usage leads to tolerance and addiction. Together, these factors contribute to significant opioid crisis in the United States, causing more than 75,000 annual opioids overdose deaths in recent years. The purpose of this proposal is to develop novel, non-opioid candidate compounds for a novel target, GPR171, for the treatment of chronic pain. GPR171 is a recently deorphanized G protein-coupled receptor (GPCR) and is expressed in tissues critical for pain signal transmission and modulation, such as periaqueductal gray in central nervous system and dorsal root ganglion in peripheral nervous system. GPR171’s activity regulates the function of nociceptive neurons, making it a potential target for pain management. In animal models for nociceptive pain, inflammatory pain, neuropathic pain and postoperative pain, activation of GPR171 significantly reduced pain related behaviors. No reinforcing properties were detected at functional dose, and evidences suggest that peripheral activation of GPR171 is sufficient to be efficacious. Currently, there are only two small molecule ligands known for GPR171, both with modest potency and efficacy. To fully realize the potential for GPR171 to be a target for chronic pain treatment, it is critical to discover and develop additional GPR171 ligands as tool compounds and therapeutic candidates. Based on our expertise in GPCR biochemistry, structural biology and pharmacology, we propose to use DNA-encoded library screening and structure-based virtual screening to identify novel hit compounds and verify them experimentally. This proposal is in response to funding opportunity announcement RFA-NS-20-011, entitled “HEAL INITIATIVE: Development of Therapies and Technologies Directed at Enhanced Pain Management (R43/R44 - Clinical Trial Not Allowed)”.