893990-34-6

VU0240551 is a K⁺/Cl^- cotransporter 2 (KCC2) inhibitor (IC₅₀ = 568 nM). It selectively inhibits KCC2 over Na⁺/K⁺/Cl^- cotransporter 1 (NKCC1; IC₅₀ = >50 μM) but does inhibit the activity of adenosine A₁ and A₃ receptors, as well as inhibits activity of L-type calcium channels at the benzothiazepine site and human ether-a-go-go-related gene (hERG) potassium channels by greater than 50% in a panel of 68 receptors, ion channels, and transporters at 10 μM. VU0240551 decreases potassium ion uptake by 70% in HEK293 cells expressing KCC2 when used at a concentration of 1 μM.

This molecule acts as an inhibitor of the K-Cl cotransporter KCC2, which is primarily responsible for maintaining intracellular Cl- concentrations including regulating an excess or lack of ions follow ing periods of under or overstimulation, as well as general dendritic development.

ChEBI: N-(4-methyl-2-thiazolyl)-2-[(6-phenyl-3-pyridazinyl)thio]acetamide is a member of pyridazines and a ring assembly.

VU0240551 is a potent, selective KCC2 inhibitor. KCC2 is a potassium-chloride exchanger expressed specifically in neurons. KCC2 functions to lower intracellular chloride concentrations below the electrochemical potential of the cells, thereby increasing the hyperexcitability of the neurons. KCC2 activity enhances GABA and other inhibitory neurotransmission and is implicated in pain processing. VU0240551 was discovered in a high-throughput screen, followed by directed medicinal chemistry. VU0240551 is selective for KCC2 over NKCC1. VU0240551 binds competitively to the K+ site and binds noncompetitively to the Cl- site. VU0240551 is the only small molecule with specificity for a KCC family member.

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[1] ERIC DELPIRE. Small-molecule screen identifies inhibitors of the neuronal K-Cl cotransporter KCC2.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106 13: 5383-5388. DOI: 10.1073/pnas.0812756106