H3R-IN-1 is an effective inverse agonist of the histamine receptor 3 (H3R).

H3R-IN-1, an H3R inverse agonist, effectively induces differentiation of oligodendrocyte precursor cells (OPC) in a dose-dependent manner with an EC 50 of 25 nM. Western blot analysis shows marked elevation in the protein levels of myelin-associated glycoprotein (MAG) and myelin basic protein (MBP) in differentiating OPCs following exposure to H3R-IN-1. This enhancement indicates that H3R-IN-1 facilitates the maturation of more OPCs. Additionally, H3R-IN-1 escalates the level of Forskolin-stimulated cAMP in primary OPCs dose-dependently.

The efficacy of H3R-IN-1 in promoting in vivo remyelination is evaluated using the Cuprizone/Rapamycin-induced demyelination model. In this model, mice undergo a 5-week regimen of a Cuprizone-laced diet coupled with intraperitoneal Rapamycin injections, followed by a 9-day treatment with H3R-IN-1. The combined treatment of Cuprizone diet and Rapamycin injections results in significant demyelination in the corpus callosum and cortex. Subsequently, administering H3R-IN-1 (30 mg/kg, 9 days) markedly enhances the density of myelin-specific Black-gold II staining in these brain regions compared to the vehicle control group, indicating improved remyelination.