VU 0240551

VU 0240551 is a small-molecule inhibitor of KCC2 with IC50 value of 560nM [1].

KCC2 is one of the K+-Cl+ cotransporters and is exclusively expressed in CNS neurons. KCC2 transports Cl+ in an electroneutral way and plays a key role in maintaining intracellular Cl+ concentration in neurons. VU 0240551 is screened out from a library of 234,000 small molecules by tested in HEK293 cells overexpressing KCC2. VU 0240551 potently inhibits KCC2 with IC50 value of 560nM while shows minimal effect on NKCC1. VU 0240551 at concentration of 5μM inhibits 12.9% activity of NKCC1. Besides that, VU 0240551 significantly inhibits KCC2-mediated K+ uptake at concentration of 10μM. VU 0240551 is also found to inhibit KCC3 in the micromolar range. Moreover, when treated with some other GPCRs, ion channels and transporters, VU 0240551 exerts significant effects on Adenosine A1 and A3 receptors, L- type Ca2+ channel and K+ channel hERG [1, 2].

References:
[1] Delpire E, Days E, Lewis L M, et al. Small-molecule screen identifies inhibitors of the neuronal K-Cl cotransporter KCC2. Proceedings of the National Academy of Sciences, 2009, 106(13): 5383-5388.
[2] Friauf E, Rust M B, Schulenborg T, et al. Chloride cotransporters, chloride homeostasis, and synaptic inhibition in the developing auditory system. Hearing research, 2011, 279(1): 96-110.

[Lessons learned from the evacuation of the VU University Medical Centre after flooding].[Pubmed:28224872]

Ned Tijdschr Geneeskd. 2017;161:D861.

On 8 September 2015, flooding of the lower floors of the VU University Medical Center in Amsterdam caused serious damage to many vital technical services, such as water and power supplies. The decision was made to completely evacuate the university hospital. This paper describes the chronology and events of that day and shares a number of important lessons that were learned, in order to help readers to optimise crisis organisation in their own institutions. A serious situation or disaster can never be standardised in protocols or manuals; flexibility, improvisation and confidence in one another's expertise and commitment are therefore essential.

Effects of VU0240551, a novel KCC2 antagonist, and DIDS on chloride homeostasis of neocortical neurons from rats and humans.[Pubmed:25086309]

Neuroscience. 2014 Sep 26;277:831-41.

The normal function of GABAA receptor-mediated inhibition is governed by several factors, including release of GABA, subunit composition and density of the receptors and in particular by the appropriate ionic gradient. In the human epileptogenic neocortex an impaired chloride (Cl(-)) gradient has been proposed, due to decreases of potassium-coupled chloride transport (KCC2) and voltage-gated Cl(-) channels (ClC). Regarding sodium- and potassium-coupled Cl(-) transport (NKCC1) both up- and downregulations have been proposed. We investigated changes of Cl(-) homeostasis of human and rat neocortical neurons (layer 2/3) with intracellular recordings and iontophoretic Cl(-) loading employing selective compounds. After cessation of iontophoresis, the IPSPA amplitudes of rat neurons recovered with a time constant (taurec) of 6.5s (n=21). In human neurons, taurec averaged 17.8s (n=36; 23 resections). Application of the novel KCC2 blocker VU0240551 (1 muM) caused in rat neurons a reversible prolongation of taurec from 5.7 to 8.1s (n=11), corresponding to a VU0240551-sensitive Cl(-) transport rate (1/Deltataurec) of 0.0504s(-1). In human neurons, taurec increased on application of 1muM VU0240551, on average from 15.1 to 20.3s (n=17). The human neurons comprised two subgroups with different taurec when segregated according to a border given by the mean+2s.d. of rat neurons. In one group, taurec averaged 8.7s (n=6) and reversibly increased to 14.6s in the presence of 1muM VU0240551, corresponding to a Cl(-) transport rate of 0.0504s(-1). The other group had an average taurec of 18.5s which increased in the presence of 1muM VU0240551 to 23.3s (n=11), indicating a much smaller rate (0.0151s(-1)). Addition of DIDS, a presumed blocker of anion exchanger (AE), increased the taurec of rat neurons from 7.5 to 8.8s (n=6) corresponding to a DIDS-sensitive rate of 0.0185s(-1). In human neurons, DIDS increased taurec from 23.3 to 50.7s (n=7), corresponding to a DIDS-sensitive rate of 0.0200s(-1). These data suggest a greatly reduced KCC2-mediated transport rate in most of the human neurons. The two subgroups observed in human tissue indicate a considerable variability of Cl(-) transport within a given tissue from almost normal to greatly impeded, predominated by a decline of KCC2 whereas AE is unaltered.

Further optimization of the K-Cl cotransporter KCC2 antagonist ML077: development of a highly selective and more potent in vitro probe.[Pubmed:22727639]

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4532-5.

Further chemical optimization of the MLSCN/MLPCN probe ML077 (KCC2 IC(50)=537 nM) proved to be challenging as the effort was characterized by steep SAR. However, a multi-dimensional iterative parallel synthesis approach proved productive. Herein we report the discovery and SAR of an improved novel antagonist (VU0463271) of the neuronal-specific potassium-chloride cotransporter 2 (KCC2), with an IC(50) 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.

Small-molecule screen identifies inhibitors of the neuronal K-Cl cotransporter KCC2.[Pubmed:19279215]

Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5383-8.

KCC2, a neuronal-specific K-Cl cotransporter, plays a major role in maintaining intracellular Cl(-) concentration in neurons below its electrochemical equilibrium potential, thus favoring robust GABA hyperpolarizing or inhibitory responses. The pharmacology of the K-Cl cotransporter is dominated by loop diuretics such as furosemide and bumetanide, molecules used in clinical medicine because they inhibit the loop of Henle Na-K-2Cl cotransporter with much higher affinity. To identify molecules that affect KCC2 activity, we developed a fluorescence-based assay suitable for high-throughput screening (HTS) and used the assay to screen a library of 234,000 small molecules. We identified a large number of molecules that either decrease or increase the activity of the cotransporter. Here, we report the characterization of a small number of inhibitors, some of which inhibit KCC2 activity in the submicomolar range without substantially affecting NKCC1 activity. Using medicinal chemistry, we synthesized a number of variants, tested their effect on KCC2 function, and provide an analysis of structure/activity relationships. We also used one of the compounds to demonstrate competitive inhibition in regard to external [K(+)] versus noncompetitive inhibition in respect to external [Cl(-)].

VU 0240551 is a small molecule inhibitor of the neuronal K-Cl cotransporter, KCC2 (IC50 = 560 nM for K+ uptake assay in KCC2-overexpressing cells).

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