VU0463271quarterhydrate是神经特异性氯钾协同转运蛋白2(KCC2)的有效抑制剂，其IC50值为61nM。
VU0463271 quarterhydrate is a potent KCC2 antagonist, with an IC50 of 61 nM[1].
VU0463271 is a potent antagonist of the neuronal-specific potassium-chloride cotransporter 2 (KCC2), with an IC50 of 61 nM and >100-fold selectivity versus the closely related Na-K-2Cl cotransporter 1 (NKCC1) and no activity in a larger panel of GPCRs, ion channels and transporters. It is also found rapidly cleared in vitro[1].VU0463271 is applied to the transected CNS preparation and resulted in a significant increase in firing rates of the Drosophila CNS with 1 μM VU0463271 resulting in a peak firing rate that was a 2.7- and 2.5-fold increase over baseline firing rate for OR and rdl strains, respectively[2].VU0463271 (10-100 nM) results in approximately 20% reduction of CNS firing frequency within asmall percentage of preparations[2].
VU0463271 is found to be a moderate-to-high clearance compound in rat (CL=57 mL/min/kg) following intravenous administration (1 mg/kg); the low volume of distribution at steady state (Vss 0.4 L/kg), coupled with moderate-to-high clearance produce a relatively short t1/2 (9 min) in vivo[1].
[1]. Delpire E, et al. Further optimization of the K-Cl cotransporter KCC2 antagonist ML077: development of a highly selective and more potent in vitro probe. Bioorg Med Chem Lett. 2012 Jul 15;22(14):4532-5. [2]. Rui Chen, et al. Functional Coupling of K +-Cl - Cotransporter (KCC) to GABA-Gated Cl - Channels in the Central Nervous System of Drosophila melanogaster Leads to Altered Drug Sensitivities. ACS Chem Neurosci. 2019 Jun 19;10(6):2765-2776.
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