Cinnamyl-driven GPR183 antagonists: Scaffold optimization toward non-opioid pain therapy

GPR183, a G protein-coupled receptor, has been implicated in the development and progression of neuropathic pain. Herein, we report the identification and characterization of a GPR183 antagonist, SLU-0012011. This compound inhibited GPR183 activation in a calcium mobilization assay and reduced CCI-induced mechano-allodynia in mice without observable toxicity. Additionally, SLU-0012011 demonstrated favorable metabolic stability, with a half-life of 116.8 minutes and limited inhibition of key cytochrome P450 isozymes. These findings support further investigation of SLU-0012011 as a potential lead compound for the treatment of neuropathic pain.