PIPE-3297 (compound 25) is a selective kappa opioid receptor (KOR) agonist that activates the G protein signaling pathway with an EC50 of 1.1 nM and exhibits low β-arrestin-2 recruitment activity (10%). Additionally, PIPE-3297 promotes myelination and has anti-inflammatory properties.

κ Opioid Receptor:1.1 nM (EC50)

PIPE-3297 (0.5-1 μM) triggers myelination and promotes the differentiation of oligodendrocyte precursor cells (OPC) into oligodendrocytes (OL). However, PIPE-3297 is cardiotoxic, inhibiting the hERG potassium ion channel with an efficiency of 72% at 3 μM, and demonstrates instability in liver microsomes.

Administering a single subcutaneous dose of PIPE-3297 (30 mg/kg) leads to a 90% occupancy of KOR in the CNS, with brain concentrations reaching 12.5 μM. In C57BL/6 mice, there is no evidence of KOR-mediated hypokinesis. In the same mouse model, PIPE-3297 induces KOR-dependent differentiation of OPCs into mature OL cells. Furthermore, treatment with PIPE-3297 (3 and 30 mg/kg, subcutaneously, for 23 days) alleviates MOG-induced autoimmune encephalomyelitis (EAE) in C57BL/6 mice.