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

Lars Jørgensen; Anas Al-Khawaja; Stefanie Kickinger; Stine B Vogensen; Jonas Skovgaard-Petersen; Emil Rosenthal; Nrupa Borkar; Rebekka Löffler; Karsten K Madsen; Hans Bräuner-Osborne; Arne Schousboe; Gerhard F Ecker; Petrine Wellendorph; Rasmus P Clausen

doi:10.1021/acs.jmedchem.7b00924

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

Lars Jørgensen, Anas Al-Khawaja, Stefanie Kickinger, Stine B Vogensen, Jonas Skovgaard-Petersen, Emil Rosenthal, Nrupa Borkar, Rebekka Löffler, Karsten K Madsen, Hans Bräuner-Osborne, Arne Schousboe, Gerhard F Ecker, Petrine Wellendorph, Rasmus P Clausen

13 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	21
Pages (from-to)	8834-8846
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.7b00924
Publication status	Published - 9 Nov 2017

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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

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 et al.
In: Journal of Medicinal Chemistry, Vol. 60, No. 21, 09.11.2017, p. 8834-8846.

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

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

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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

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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.

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

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