Development of GPR183 Antagonists to Treat Neuropathic Pain

Abstract

Chronic neuropathic pain affects millions of people in the United States today. Opioids are currently the frontline agent for the treatment of neuropathic pain; however, as their use continues to grow, serious side effects can arise including addiction and death. The need for a safer alternative to opioids is becoming increasingly more urgent. GPR183 (Ebstein‐Barr induced gene 2, EBI2) is a G‐protein coupled receptor (GPCR) that binds to 7a,25‐dihydroxycholesterol (7a,25‐OHC). A homology model for GPR183 was constructed and a pharmacophore hypothesis was built around the binding of other known ligands to the receptor. Over 5 million compounds were screened in silico for their similarity to our pharmacophore hypothesis and the top 20k hits were funneled into a high‐throughput docking protocol. Several compounds showed strong inhibition of 7a,25‐OHC calcium mobilization with nanomolar potency. Intrathecal injections of these GPR183 antagonists reversed CCI‐induced mechano‐allodynia in mice when given at peak neuropathic pain. These results identify a prominent and functional role for GPR183 in the spinal cord in the maintenance of neuropathic pain. A preliminary structure‐activity relationship study of one of these compounds is being performed to study the pharmacology and medicinal properties of this new class of compounds. Support or Funding Information We would like to acknowledge Dr. Dale Dorsett and the Saint Louis University Genomics Core Facility for their assistance with the RNA‐Sequencing. This research was supported by funds from Dr. Salvemini and Dr. Arnatt and T32 GM008306‐01 training grant (KB). Dr. Salvemini and Dr. Arnatt have filed a patent describing the intellectual property generated at SLU. All other authors claim no conflict of interest.

The genetics of asthma and the promise of genomics-guided drug target discovery

“…Both drugs are GPR183 antagonists and are being tested as a treatment for neuropathic pain. 76 Integrin subunit β-8 (ITGb-8) is a protein encoded by ITGB8. This subunit associates with integrin subunit α-V to form a heterodimer receptor complex called integrin αvβ8, which is expressed on airway epithelial cells and fibroblasts.…”