GSK239512

GSK239512 is a blood-brain barrier-permeable, orally active H3 receptor antagonist, with a human pK_i ranging from <5.5 to 9.92 and a murine pK_i ranging from 9.44 to 9.83. GSK239512 modulates cholinergic and monoaminergic neurotransmission, blocks the inhibitory feedback of H3 receptors, and increases the release of pro-cognitive neurotransmitters. GSK239512 induces oligodendrocyte precursor cell differentiation and restores myelin gene expression at the cellular level. GSK239512 reverses Scopolamine (HY-N0296)-induced memory deficits and improves recognition memory in animal models. GSK239512 can be used in research related to Alzheimer's disease, chronic traumatic encephalopathy, relapsing-remitting multiple sclerosis, and schizophrenia^{[1][2][3][4][5][6]}. In Vitro:GSK239512 (10 μM; 5 days) promotes the differentiation of primary rat oligodendrocyte precursor cells into mature oligodendrocytes^[2][3].
GSK239512 potently binds to human and rat H₃ receptors in native cerebral cortex membranes and recombinant HEK-293 cells, with pK_i values ranging from 9.44 to 9.92, and exhibits over 1000-fold selectivity over other protein targets^[6].
GSK239512 exhibits favorable in vitro druggability profiles, including extremely weak hERG inhibitory effect, no cytochrome P450 inhibitory activity, high water solubility, moderate binding affinity to human serum albumin, and good metabolic stability in rat and human liver microsomes^[6]. In Vivo:GSK239512 (10 mg/kg; p.o.; twice daily; 1 month) restores the expression of some myelin-related genes in rmTBI-injured Tau58.4 mice, but fails to repair white matter damage at the histopathological level^[2].
GSK239512 (0.3-3 mg/kg; p.o.) significantly reverses scopolamine (HY-N0296)-induced cognitive impairment in rats at doses of 1 mg/kg and 3 mg/kg (p.o.)^[6].
GSK239512 (0.04-3 mg/kg; p.o.) achieves significant occupancy of histamine H₃ receptors in the rat cortex, with an estimated EC₅₀ value of 0.015 μM; it also significantly reverses polydipsia induced by H3 agonists in rats, with an ED₅₀ of 0.04 mg/kg^[6].