GPR37L1 agonist P06 is a potent, small-molecule agonist of G protein-coupled receptor GPR37-like 1 (GPR37L1), induces dose-dependent potassium influx with EC50 of 182.4 nM in thallium (Tl+) influx assay using HEK293 cells expressing GPR37L1 and the KCNJ3 channel, exhibits significant analgesic effects.
P06 exhibits the strong predicted binding affinity (ΔG = −9.94 kcal/mol).
P06 mitigates PTX-induced mechanical allodynia without affecting motor function.
P06 activates GPR37L1 and preferentially signals through the Gβγ pathway to modulate ion channel function.
P06 (3.6 μg) alleviates mechanical allodynia in the spared nerve injury (SNI) model.
P06 reduces nerve injury–induced SGC and macrophage activation in dorsal root ganglia.
P06 regulates IL-1β release and potassium homeostasis in mouse and human SGC cultures.
GPR37L1 is a glia-selective receptor expressed in astrocytes and satellite glial cells (SGCs), and GPR37L1 protects against the development of neuropathic pain.
GPR37L1 regulates the function of inwardly rectifying potassium channels (e.g., Kir4.1) in SGCs.