Identification of the first highly selective inhibitor of human GABA transporter GAT3

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Identification of the first highly selective inhibitor of human GABA transporter GAT3. / Damgaard, Maria; Al-Khawaja, Anas; Vogensen, Stine B.; Jurik, A; Sijm, M; Lie, M; Bæk, M.I.; Rosenthal, Emil; Jensen, Anders A.; Ecker, G.F.; Frølund, Bente; Wellendorph, Petrine; Clausen, Rasmus P.

In: A C S Chemical Neuroscience, Vol. 6, 2015, p. 1591-1599.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Damgaard, M, Al-Khawaja, A, Vogensen, SB, Jurik, A, Sijm, M, Lie, M, Bæk, MI, Rosenthal, E, Jensen, AA, Ecker, GF, Frølund, B, Wellendorph, P & Clausen, RP 2015, 'Identification of the first highly selective inhibitor of human GABA transporter GAT3', A C S Chemical Neuroscience, vol. 6, pp. 1591-1599. https://doi.org/10.1021/acschemneuro.5b00150

APA

Damgaard, M., Al-Khawaja, A., Vogensen, S. B., Jurik, A., Sijm, M., Lie, M., Bæk, M. I., Rosenthal, E., Jensen, A. A., Ecker, G. F., Frølund, B., Wellendorph, P., & Clausen, R. P. (2015). Identification of the first highly selective inhibitor of human GABA transporter GAT3. A C S Chemical Neuroscience, 6, 1591-1599. https://doi.org/10.1021/acschemneuro.5b00150

Vancouver

Damgaard M, Al-Khawaja A, Vogensen SB, Jurik A, Sijm M, Lie M et al. Identification of the first highly selective inhibitor of human GABA transporter GAT3. A C S Chemical Neuroscience. 2015;6:1591-1599. https://doi.org/10.1021/acschemneuro.5b00150

Author

Damgaard, Maria ; Al-Khawaja, Anas ; Vogensen, Stine B. ; Jurik, A ; Sijm, M ; Lie, M ; Bæk, M.I. ; Rosenthal, Emil ; Jensen, Anders A. ; Ecker, G.F. ; Frølund, Bente ; Wellendorph, Petrine ; Clausen, Rasmus P. / Identification of the first highly selective inhibitor of human GABA transporter GAT3. In: A C S Chemical Neuroscience. 2015 ; Vol. 6. pp. 1591-1599.

Bibtex

@article{b35e92ce1aee449fb357089e42fe3cc6,
title = "Identification of the first highly selective inhibitor of human GABA transporter GAT3",
abstract = "Screening a library of small-molecule compounds using a cell line expressing human GABA transporter 3 (hGAT3) in a [(3)H]GABA uptake assay identified isatin derivatives as a new class of hGAT3 inhibitors. A subsequent structure-activity relationship (SAR) study led to the identification of hGAT3-selective inhibitors (i.e., compounds 20 and 34) that were superior to the reference hGAT3 inhibitor, (S)-SNAP-5114, in terms of potency (low micromolar IC50 values) and selectivity (>30-fold selective for hGAT3 over hGAT1/hGAT2/hBGT1). Further pharmacological characterization of compound 20 (5-(thiophen-2-yl)indoline-2,3-dione) revealed a noncompetitive mode of inhibition at hGAT3. This suggests that this compound class, which has no structural resemblance to GABA, has a binding site different from the substrate, GABA. This was supported by a molecular modeling study that suggested a unique binding site that matched the observed selectivity, inhibition kinetics, and SAR of the compound series. These compounds are the most potent GAT3 inhibitors reported to date that provide selectivity for GAT3 over other GABA transporter subtypes. ",
author = "Maria Damgaard and Anas Al-Khawaja and Vogensen, {Stine B.} and A Jurik and M Sijm and M Lie and M.I. B{\ae}k and Emil Rosenthal and Jensen, {Anders A.} and G.F. Ecker and Bente Fr{\o}lund and Petrine Wellendorph and Clausen, {Rasmus P.}",
year = "2015",
doi = "10.1021/acschemneuro.5b00150",
language = "English",
volume = "6",
pages = "1591--1599",
journal = "ACS Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",

}

RIS

TY - JOUR

T1 - Identification of the first highly selective inhibitor of human GABA transporter GAT3

AU - Damgaard, Maria

AU - Al-Khawaja, Anas

AU - Vogensen, Stine B.

AU - Jurik, A

AU - Sijm, M

AU - Lie, M

AU - Bæk, M.I.

AU - Rosenthal, Emil

AU - Jensen, Anders A.

AU - Ecker, G.F.

AU - Frølund, Bente

AU - Wellendorph, Petrine

AU - Clausen, Rasmus P.

PY - 2015

Y1 - 2015

N2 - Screening a library of small-molecule compounds using a cell line expressing human GABA transporter 3 (hGAT3) in a [(3)H]GABA uptake assay identified isatin derivatives as a new class of hGAT3 inhibitors. A subsequent structure-activity relationship (SAR) study led to the identification of hGAT3-selective inhibitors (i.e., compounds 20 and 34) that were superior to the reference hGAT3 inhibitor, (S)-SNAP-5114, in terms of potency (low micromolar IC50 values) and selectivity (>30-fold selective for hGAT3 over hGAT1/hGAT2/hBGT1). Further pharmacological characterization of compound 20 (5-(thiophen-2-yl)indoline-2,3-dione) revealed a noncompetitive mode of inhibition at hGAT3. This suggests that this compound class, which has no structural resemblance to GABA, has a binding site different from the substrate, GABA. This was supported by a molecular modeling study that suggested a unique binding site that matched the observed selectivity, inhibition kinetics, and SAR of the compound series. These compounds are the most potent GAT3 inhibitors reported to date that provide selectivity for GAT3 over other GABA transporter subtypes.

AB - Screening a library of small-molecule compounds using a cell line expressing human GABA transporter 3 (hGAT3) in a [(3)H]GABA uptake assay identified isatin derivatives as a new class of hGAT3 inhibitors. A subsequent structure-activity relationship (SAR) study led to the identification of hGAT3-selective inhibitors (i.e., compounds 20 and 34) that were superior to the reference hGAT3 inhibitor, (S)-SNAP-5114, in terms of potency (low micromolar IC50 values) and selectivity (>30-fold selective for hGAT3 over hGAT1/hGAT2/hBGT1). Further pharmacological characterization of compound 20 (5-(thiophen-2-yl)indoline-2,3-dione) revealed a noncompetitive mode of inhibition at hGAT3. This suggests that this compound class, which has no structural resemblance to GABA, has a binding site different from the substrate, GABA. This was supported by a molecular modeling study that suggested a unique binding site that matched the observed selectivity, inhibition kinetics, and SAR of the compound series. These compounds are the most potent GAT3 inhibitors reported to date that provide selectivity for GAT3 over other GABA transporter subtypes.

U2 - 10.1021/acschemneuro.5b00150

DO - 10.1021/acschemneuro.5b00150

M3 - Journal article

VL - 6

SP - 1591

EP - 1599

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

ER -

ID: 141054461