Binding of Mazindol and Analogs to the human Serotonin and Dopamine Transporters

Kasper Severinsen; Heidi Koldso; Katrine Almind Vinberg Thorup; Christina Schjoth-Eskesen; Pernille Thornild Moller; Ove Wiborg; Henrik Helligso Jensen; Steffen Sinning; Birgit Schiott

doi:10.1124/mol.113.088922

Binding of Mazindol and Analogs to the human Serotonin and Dopamine Transporters

Kasper Severinsen, Heidi Koldso, Katrine Almind Vinberg Thorup, Christina Schjoth-Eskesen, Pernille Thornild Moller, Ove Wiborg, Henrik Helligso Jensen, Steffen Sinning, Birgit Schiott

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

22 Citations (Scopus)

Abstract

Mazindol has been explored as a possible agent in cocaine addiction pharmacotherapy. The tricyclic compound inhibits both the dopamine transporter and the serotonin transporter and simple chemical modifications alters target selectivity considerably. Mazindol is therefore an attractive scaffold for both understanding the molecular determinants of serotonin/dopamine transporter selectivity and for the development of novel drug abuse treatments. Using molecular modeling and pharmacological profiling of rationally chosen serotonin and dopamine transporter mutants with respect to a series of mazindol analogues has allowed us to determine the orientation of mazindol within the central binding site. We find that mazindol binds in the central substrate binding site, and that the transporter selectivity can be modulated through mutations of a few residues in the binding pocket. Mazindol is most likely to bind as the S-enantiomer. Tyrosines 95 and 175 in the human serotonin transporter and the corresponding phenylalanines 75 and 155 in the human dopamine transporter are the primary determinants of mazindol selectivity. Manipulating the interaction of substituents on the 7-position with the human serotonin transporter Tyr175 / dopamine transporter Phe155 is found to be a strong tool in tuning the selectivity of mazindol analogs and may be utilized in future drug design of cocaine abuse pharmacotherapies.

Original language	English
Journal	Molecular Pharmacology
Volume	85
Issue	2
Pages (from-to)	208-17
ISSN	0026-895X
DOIs	https://doi.org/10.1124/mol.113.088922
Publication status	Published - Feb 2014

Access to Document

10.1124/mol.113.088922

Cite this

@article{98a9d367ee584d0285a88a469d1e8d57,

title = "Binding of Mazindol and Analogs to the human Serotonin and Dopamine Transporters",

abstract = "Mazindol has been explored as a possible agent in cocaine addiction pharmacotherapy. The tricyclic compound inhibits both the dopamine transporter and the serotonin transporter and simple chemical modifications alters target selectivity considerably. Mazindol is therefore an attractive scaffold for both understanding the molecular determinants of serotonin/dopamine transporter selectivity and for the development of novel drug abuse treatments. Using molecular modeling and pharmacological profiling of rationally chosen serotonin and dopamine transporter mutants with respect to a series of mazindol analogues has allowed us to determine the orientation of mazindol within the central binding site. We find that mazindol binds in the central substrate binding site, and that the transporter selectivity can be modulated through mutations of a few residues in the binding pocket. Mazindol is most likely to bind as the S-enantiomer. Tyrosines 95 and 175 in the human serotonin transporter and the corresponding phenylalanines 75 and 155 in the human dopamine transporter are the primary determinants of mazindol selectivity. Manipulating the interaction of substituents on the 7-position with the human serotonin transporter Tyr175 / dopamine transporter Phe155 is found to be a strong tool in tuning the selectivity of mazindol analogs and may be utilized in future drug design of cocaine abuse pharmacotherapies.",

author = "Kasper Severinsen and Heidi Koldso and Thorup, {Katrine Almind Vinberg} and Christina Schjoth-Eskesen and Moller, {Pernille Thornild} and Ove Wiborg and Jensen, {Henrik Helligso} and Steffen Sinning and Birgit Schiott",

year = "2014",

month = feb,

doi = "10.1124/mol.113.088922",

language = "English",

volume = "85",

pages = "208--17",

journal = "Molecular Pharmacology",

issn = "0026-895X",

publisher = "Elsevier Inc.",

number = "2",

}

Binding of Mazindol and Analogs to the human Serotonin and Dopamine Transporters. / Severinsen, Kasper; Koldso, Heidi; Thorup, Katrine Almind Vinberg et al.
In: Molecular Pharmacology, Vol. 85, No. 2, 02.2014, p. 208-17.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Binding of Mazindol and Analogs to the human Serotonin and Dopamine Transporters

AU - Severinsen, Kasper

AU - Koldso, Heidi

AU - Thorup, Katrine Almind Vinberg

AU - Schjoth-Eskesen, Christina

AU - Moller, Pernille Thornild

AU - Wiborg, Ove

AU - Jensen, Henrik Helligso

AU - Sinning, Steffen

AU - Schiott, Birgit

PY - 2014/2

Y1 - 2014/2

N2 - Mazindol has been explored as a possible agent in cocaine addiction pharmacotherapy. The tricyclic compound inhibits both the dopamine transporter and the serotonin transporter and simple chemical modifications alters target selectivity considerably. Mazindol is therefore an attractive scaffold for both understanding the molecular determinants of serotonin/dopamine transporter selectivity and for the development of novel drug abuse treatments. Using molecular modeling and pharmacological profiling of rationally chosen serotonin and dopamine transporter mutants with respect to a series of mazindol analogues has allowed us to determine the orientation of mazindol within the central binding site. We find that mazindol binds in the central substrate binding site, and that the transporter selectivity can be modulated through mutations of a few residues in the binding pocket. Mazindol is most likely to bind as the S-enantiomer. Tyrosines 95 and 175 in the human serotonin transporter and the corresponding phenylalanines 75 and 155 in the human dopamine transporter are the primary determinants of mazindol selectivity. Manipulating the interaction of substituents on the 7-position with the human serotonin transporter Tyr175 / dopamine transporter Phe155 is found to be a strong tool in tuning the selectivity of mazindol analogs and may be utilized in future drug design of cocaine abuse pharmacotherapies.

AB - Mazindol has been explored as a possible agent in cocaine addiction pharmacotherapy. The tricyclic compound inhibits both the dopamine transporter and the serotonin transporter and simple chemical modifications alters target selectivity considerably. Mazindol is therefore an attractive scaffold for both understanding the molecular determinants of serotonin/dopamine transporter selectivity and for the development of novel drug abuse treatments. Using molecular modeling and pharmacological profiling of rationally chosen serotonin and dopamine transporter mutants with respect to a series of mazindol analogues has allowed us to determine the orientation of mazindol within the central binding site. We find that mazindol binds in the central substrate binding site, and that the transporter selectivity can be modulated through mutations of a few residues in the binding pocket. Mazindol is most likely to bind as the S-enantiomer. Tyrosines 95 and 175 in the human serotonin transporter and the corresponding phenylalanines 75 and 155 in the human dopamine transporter are the primary determinants of mazindol selectivity. Manipulating the interaction of substituents on the 7-position with the human serotonin transporter Tyr175 / dopamine transporter Phe155 is found to be a strong tool in tuning the selectivity of mazindol analogs and may be utilized in future drug design of cocaine abuse pharmacotherapies.

U2 - 10.1124/mol.113.088922

DO - 10.1124/mol.113.088922

M3 - Journal article

C2 - 24214825

SN - 0026-895X

VL - 85

SP - 208

EP - 217

JO - Molecular Pharmacology

JF - Molecular Pharmacology

IS - 2

ER -

Binding of Mazindol and Analogs to the human Serotonin and Dopamine Transporters

Abstract

Access to Document

Fingerprint

Cite this