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)”.