Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters. / Andersen, Jacob; Stuhr-Hansen, Nicolai; Zachariassen, Linda; Toubro, Søren; Hansen, Stinna Maria R; Eildal, Jonas Nii Nortey; Bond, Andrew D; Bøgesø, Klaus P; Bang-Andersen, Benny; Kristensen, Anders Skov; Strømgaard, Kristian.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 29, 19.07.2011, p. 12137-12142.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Andersen, J, Stuhr-Hansen, N, Zachariassen, L, Toubro, S, Hansen, SMR, Eildal, JNN, Bond, AD, Bøgesø, KP, Bang-Andersen, B, Kristensen, AS & Strømgaard, K 2011, 'Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 29, pp. 12137-12142. https://doi.org/10.1073/pnas.1103060108

APA

Andersen, J., Stuhr-Hansen, N., Zachariassen, L., Toubro, S., Hansen, S. M. R., Eildal, J. N. N., ... Strømgaard, K. (2011). Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters. Proceedings of the National Academy of Sciences of the United States of America, 108(29), 12137-12142. https://doi.org/10.1073/pnas.1103060108

Vancouver

Andersen J, Stuhr-Hansen N, Zachariassen L, Toubro S, Hansen SMR, Eildal JNN et al. Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters. Proceedings of the National Academy of Sciences of the United States of America. 2011 Jul 19;108(29):12137-12142. https://doi.org/10.1073/pnas.1103060108

Author

Andersen, Jacob ; Stuhr-Hansen, Nicolai ; Zachariassen, Linda ; Toubro, Søren ; Hansen, Stinna Maria R ; Eildal, Jonas Nii Nortey ; Bond, Andrew D ; Bøgesø, Klaus P ; Bang-Andersen, Benny ; Kristensen, Anders Skov ; Strømgaard, Kristian. / Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 29. pp. 12137-12142.

Bibtex

@article{9d30b7294c5348aca45b64c7541aee66,
title = "Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters",
abstract = "Inhibitors of the serotonin transporter (SERT) and norepinephrine transporter (NET) are widely used in the treatment of major depressive disorder. Although SERT/NET selectivity is a key determinant for the therapeutic properties of these drugs, the molecular determinants defining SERT/NET selectivity are poorly understood. In this study, the structural basis for selectivity of the SERT selective inhibitor citalopram and the structurally closely related NET selective inhibitor talopram is delineated. A systematic structure-activity relationship study allowed identification of the substituents that control activity and selectivity toward SERT and NET and revealed a common pattern showing that SERT and NET have opposite preference for the stereochemical configuration of these inhibitors. Mutational analysis of nonconserved SERT/NET residues within the central substrate binding site was performed to determine the molecular basis for inhibitor selectivity. Changing only five residues in NET to the complementary residues in SERT transferred a SERT-like affinity profile for R- and S-citalopram into NET, showing that the selectivity of these compounds is determined by amino acid differences in the central binding site of the transporters. In contrast, the activity of R- and S-talopram was largely unaffected by any mutations within the central substrate binding site of SERT and NET and in the outer vestibule of NET, suggesting that citalopram and talopram bind to distinct sites on SERT and NET. Together, these findings provide important insight into the molecular basis for SERT/NET selectivity of antidepressants, which can be used to guide rational development of unique transporter inhibitors with fine-tuned transporter selectivity.",
keywords = "The Faculty of Pharmaceutical Sciences",
author = "Jacob Andersen and Nicolai Stuhr-Hansen and Linda Zachariassen and S{\o}ren Toubro and Hansen, {Stinna Maria R} and Eildal, {Jonas Nii Nortey} and Bond, {Andrew D} and B{\o}ges{\o}, {Klaus P} and Benny Bang-Andersen and Kristensen, {Anders Skov} and Kristian Str{\o}mgaard",
year = "2011",
month = "7",
day = "19",
doi = "10.1073/pnas.1103060108",
language = "English",
volume = "108",
pages = "12137--12142",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "29",

}

RIS

TY - JOUR

T1 - Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters

AU - Andersen, Jacob

AU - Stuhr-Hansen, Nicolai

AU - Zachariassen, Linda

AU - Toubro, Søren

AU - Hansen, Stinna Maria R

AU - Eildal, Jonas Nii Nortey

AU - Bond, Andrew D

AU - Bøgesø, Klaus P

AU - Bang-Andersen, Benny

AU - Kristensen, Anders Skov

AU - Strømgaard, Kristian

PY - 2011/7/19

Y1 - 2011/7/19

N2 - Inhibitors of the serotonin transporter (SERT) and norepinephrine transporter (NET) are widely used in the treatment of major depressive disorder. Although SERT/NET selectivity is a key determinant for the therapeutic properties of these drugs, the molecular determinants defining SERT/NET selectivity are poorly understood. In this study, the structural basis for selectivity of the SERT selective inhibitor citalopram and the structurally closely related NET selective inhibitor talopram is delineated. A systematic structure-activity relationship study allowed identification of the substituents that control activity and selectivity toward SERT and NET and revealed a common pattern showing that SERT and NET have opposite preference for the stereochemical configuration of these inhibitors. Mutational analysis of nonconserved SERT/NET residues within the central substrate binding site was performed to determine the molecular basis for inhibitor selectivity. Changing only five residues in NET to the complementary residues in SERT transferred a SERT-like affinity profile for R- and S-citalopram into NET, showing that the selectivity of these compounds is determined by amino acid differences in the central binding site of the transporters. In contrast, the activity of R- and S-talopram was largely unaffected by any mutations within the central substrate binding site of SERT and NET and in the outer vestibule of NET, suggesting that citalopram and talopram bind to distinct sites on SERT and NET. Together, these findings provide important insight into the molecular basis for SERT/NET selectivity of antidepressants, which can be used to guide rational development of unique transporter inhibitors with fine-tuned transporter selectivity.

AB - Inhibitors of the serotonin transporter (SERT) and norepinephrine transporter (NET) are widely used in the treatment of major depressive disorder. Although SERT/NET selectivity is a key determinant for the therapeutic properties of these drugs, the molecular determinants defining SERT/NET selectivity are poorly understood. In this study, the structural basis for selectivity of the SERT selective inhibitor citalopram and the structurally closely related NET selective inhibitor talopram is delineated. A systematic structure-activity relationship study allowed identification of the substituents that control activity and selectivity toward SERT and NET and revealed a common pattern showing that SERT and NET have opposite preference for the stereochemical configuration of these inhibitors. Mutational analysis of nonconserved SERT/NET residues within the central substrate binding site was performed to determine the molecular basis for inhibitor selectivity. Changing only five residues in NET to the complementary residues in SERT transferred a SERT-like affinity profile for R- and S-citalopram into NET, showing that the selectivity of these compounds is determined by amino acid differences in the central binding site of the transporters. In contrast, the activity of R- and S-talopram was largely unaffected by any mutations within the central substrate binding site of SERT and NET and in the outer vestibule of NET, suggesting that citalopram and talopram bind to distinct sites on SERT and NET. Together, these findings provide important insight into the molecular basis for SERT/NET selectivity of antidepressants, which can be used to guide rational development of unique transporter inhibitors with fine-tuned transporter selectivity.

KW - The Faculty of Pharmaceutical Sciences

U2 - 10.1073/pnas.1103060108

DO - 10.1073/pnas.1103060108

M3 - Journal article

VL - 108

SP - 12137

EP - 12142

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 29

ER -

ID: 33811926