Structure-Activity Relationship, Pharmacological Characterization, and Molecular Modeling of Noncompetitive Inhibitors of the Betaine/γ-Aminobutyric Acid Transporter 1 (BGT1)

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

Standard

Structure-Activity Relationship, Pharmacological Characterization, and Molecular Modeling of Noncompetitive Inhibitors of the Betaine/γ-Aminobutyric Acid Transporter 1 (BGT1). / Jørgensen, Lars; Al-Khawaja, Anas; Kickinger, Stefanie; Vogensen, Stine B; Skovgaard-Petersen, Jonas; Rosenthal, Emil; Borkar, Nrupa; Löffler, Rebekka; Madsen, Karsten K; Bräuner-Osborne, Hans; Schousboe, Arne; Ecker, Gerhard F; Wellendorph, Petrine; Clausen, Rasmus P.

In: Journal of Medicinal Chemistry, Vol. 60, No. 21, 09.10.2017, p. 8834-8846.

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

Harvard

Jørgensen, L, Al-Khawaja, A, Kickinger, S, Vogensen, SB, Skovgaard-Petersen, J, Rosenthal, E, Borkar, N, Löffler, R, Madsen, KK, Bräuner-Osborne, H, Schousboe, A, Ecker, GF, Wellendorph, P & Clausen, RP 2017, 'Structure-Activity Relationship, Pharmacological Characterization, and Molecular Modeling of Noncompetitive Inhibitors of the Betaine/γ-Aminobutyric Acid Transporter 1 (BGT1)', Journal of Medicinal Chemistry, vol. 60, no. 21, pp. 8834-8846. https://doi.org/10.1021/acs.jmedchem.7b00924

APA

Jørgensen, L., Al-Khawaja, A., Kickinger, S., Vogensen, S. B., Skovgaard-Petersen, J., Rosenthal, E., Borkar, N., Löffler, R., Madsen, K. K., Bräuner-Osborne, H., Schousboe, A., Ecker, G. F., Wellendorph, P., & Clausen, R. P. (2017). Structure-Activity Relationship, Pharmacological Characterization, and Molecular Modeling of Noncompetitive Inhibitors of the Betaine/γ-Aminobutyric Acid Transporter 1 (BGT1). Journal of Medicinal Chemistry, 60(21), 8834-8846. https://doi.org/10.1021/acs.jmedchem.7b00924

Vancouver

Jørgensen L, Al-Khawaja A, Kickinger S, Vogensen SB, Skovgaard-Petersen J, Rosenthal E et al. Structure-Activity Relationship, Pharmacological Characterization, and Molecular Modeling of Noncompetitive Inhibitors of the Betaine/γ-Aminobutyric Acid Transporter 1 (BGT1). Journal of Medicinal Chemistry. 2017 Oct 9;60(21):8834-8846. https://doi.org/10.1021/acs.jmedchem.7b00924

Author

Jørgensen, Lars ; Al-Khawaja, Anas ; Kickinger, Stefanie ; Vogensen, Stine B ; Skovgaard-Petersen, Jonas ; Rosenthal, Emil ; Borkar, Nrupa ; Löffler, Rebekka ; Madsen, Karsten K ; Bräuner-Osborne, Hans ; Schousboe, Arne ; Ecker, Gerhard F ; Wellendorph, Petrine ; Clausen, Rasmus P. / Structure-Activity Relationship, Pharmacological Characterization, and Molecular Modeling of Noncompetitive Inhibitors of the Betaine/γ-Aminobutyric Acid Transporter 1 (BGT1). In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 21. pp. 8834-8846.

Bibtex

@article{c66d1b3cfdcf4f39bf225d2bc415938a,
title = "Structure-Activity Relationship, Pharmacological Characterization, and Molecular Modeling of Noncompetitive Inhibitors of the Betaine/γ-Aminobutyric Acid Transporter 1 (BGT1)",
abstract = "N-(1-Benzyl-4-piperidinyl)-2,4-dichlorobenzamide 5 (BPDBA) is a noncompetitive inhibitor of the betaine/GABA transporter 1 (BGT1). We here report the synthesis and structure-activity relationship of 71 analogues. We identify 26m as a more soluble 2,4-Cl substituted 3-pyridine analogue with retained BGT1 activity and an improved off-target profile compared to 5. We performed radioligand-based uptake studies at chimeric constructs between BGT1 and GAT3, experiments with site-directed mutated transporters, and computational docking in a BGT1 homology model based on the newly determined X-ray crystal structure of the human serotonin transporter (hSERT). On the basis of these experiments, we propose a binding mode involving residues within TM10 in an allosteric site in BGT1 that corresponds to the allosteric binding pocket revealed by the hSERT crystal structure. Our study provides first insights into a proposed allosteric binding pocket in BGT1, which accommodates the binding site for a series of novel noncompetitive inhibitors.",
keywords = "Journal Article",
author = "Lars J{\o}rgensen and Anas Al-Khawaja and Stefanie Kickinger and Vogensen, {Stine B} and Jonas Skovgaard-Petersen and Emil Rosenthal and Nrupa Borkar and Rebekka L{\"o}ffler and Madsen, {Karsten K} and Hans Br{\"a}uner-Osborne and Arne Schousboe and Ecker, {Gerhard F} and Petrine Wellendorph and Clausen, {Rasmus P}",
year = "2017",
month = oct,
day = "9",
doi = "10.1021/acs.jmedchem.7b00924",
language = "English",
volume = "60",
pages = "8834--8846",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "21",

}

RIS

TY - JOUR

T1 - Structure-Activity Relationship, Pharmacological Characterization, and Molecular Modeling of Noncompetitive Inhibitors of the Betaine/γ-Aminobutyric Acid Transporter 1 (BGT1)

AU - Jørgensen, Lars

AU - Al-Khawaja, Anas

AU - Kickinger, Stefanie

AU - Vogensen, Stine B

AU - Skovgaard-Petersen, Jonas

AU - Rosenthal, Emil

AU - Borkar, Nrupa

AU - Löffler, Rebekka

AU - Madsen, Karsten K

AU - Bräuner-Osborne, Hans

AU - Schousboe, Arne

AU - Ecker, Gerhard F

AU - Wellendorph, Petrine

AU - Clausen, Rasmus P

PY - 2017/10/9

Y1 - 2017/10/9

N2 - N-(1-Benzyl-4-piperidinyl)-2,4-dichlorobenzamide 5 (BPDBA) is a noncompetitive inhibitor of the betaine/GABA transporter 1 (BGT1). We here report the synthesis and structure-activity relationship of 71 analogues. We identify 26m as a more soluble 2,4-Cl substituted 3-pyridine analogue with retained BGT1 activity and an improved off-target profile compared to 5. We performed radioligand-based uptake studies at chimeric constructs between BGT1 and GAT3, experiments with site-directed mutated transporters, and computational docking in a BGT1 homology model based on the newly determined X-ray crystal structure of the human serotonin transporter (hSERT). On the basis of these experiments, we propose a binding mode involving residues within TM10 in an allosteric site in BGT1 that corresponds to the allosteric binding pocket revealed by the hSERT crystal structure. Our study provides first insights into a proposed allosteric binding pocket in BGT1, which accommodates the binding site for a series of novel noncompetitive inhibitors.

AB - N-(1-Benzyl-4-piperidinyl)-2,4-dichlorobenzamide 5 (BPDBA) is a noncompetitive inhibitor of the betaine/GABA transporter 1 (BGT1). We here report the synthesis and structure-activity relationship of 71 analogues. We identify 26m as a more soluble 2,4-Cl substituted 3-pyridine analogue with retained BGT1 activity and an improved off-target profile compared to 5. We performed radioligand-based uptake studies at chimeric constructs between BGT1 and GAT3, experiments with site-directed mutated transporters, and computational docking in a BGT1 homology model based on the newly determined X-ray crystal structure of the human serotonin transporter (hSERT). On the basis of these experiments, we propose a binding mode involving residues within TM10 in an allosteric site in BGT1 that corresponds to the allosteric binding pocket revealed by the hSERT crystal structure. Our study provides first insights into a proposed allosteric binding pocket in BGT1, which accommodates the binding site for a series of novel noncompetitive inhibitors.

KW - Journal Article

U2 - 10.1021/acs.jmedchem.7b00924

DO - 10.1021/acs.jmedchem.7b00924

M3 - Journal article

C2 - 28991462

VL - 60

SP - 8834

EP - 8846

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 21

ER -

ID: 184712377