Binding and Orientation of Tricyclic Antidepressants within the Central Substrate Site of the Human Serotonin Transporter

Sinning, Steffen; Musgaard, Maria; Jensen, Marie P.; Severinsen, Kasper; Celik, Leyla; Koldsø, Heidi; Meyer, Tine; Bols, Mikael; Jensen, Hans Jørgen; Schiøtt, Birgit; Wiborg, Ove

doi:10.1074/jbc.m109.045401

Cited by 87 publications

(144 citation statements)

References 42 publications

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“…5-HT, the natural substrate of SERT, and amphetamines such as 4-MTA interact with residues Ala96, Asp98 and Phe335 via binding of the protonated amine (Fig. 3A), while the tricyclic antidepressant imipramine is also thought to interact strongly with the Asp98 residue 13,32,37 . A study by Koldsø et al (2010) discovered that the two enantiomers of the SSRI citalopram bind to a central binding site of the hSERT homology model with reversed orientations 38 .…”

Section: Molecular Modellingmentioning

confidence: 99%

Synthesis and serotonin transporter activity of 1,3-bis(aryl)-2-nitro-1-propenes as a new class of anticancer agents

McNamara¹,

Cloonan²,

Knox³

et al. 2011

Bioorganic & Medicinal Chemistry

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Synthesis and serotonin transporter activity of 1,3-bis(aryl)-2-nitro-1-propenes as a new class of anticancer agents, Bioorganic & Medicinal Chemistry (2010), doi: 10.1016/j.bmc.2010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. derived cell lines, whilst having no effect on 'normal' peripheral blood mononuclear cells. Such effects appear to be independent of the serotonin transporter, a high affinity target for amphetamines and independent of protein tyrosine phosphatases and tubulin dynamics both of which have been previously associated with nitrostyrene-induced cell death. We demonstrate that a number of these compounds induce caspase activation, PARP cleavage, chromatin condensation and membrane blebbing in a Burkitt's lymphoma-derived cell line, consistent with these compounds inducing apoptosis in vitro. Although no specific target has yet been identified for the action of these compounds, the cell death elicited is potent, selective and worthy of further investigation.

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Section: Molecular Modellingmentioning

confidence: 99%

Synthesis and serotonin transporter activity of 1,3-bis(aryl)-2-nitro-1-propenes as a new class of anticancer agents

McNamara¹,

Cloonan²,

Knox³

et al. 2011

Bioorganic & Medicinal Chemistry

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“…S3) (8, 10, 11). Several studies have shown that the equivalent site in monoamine transporters can accommodate inhibitors (17,18,25,26), and mutations of S2 residues in SERT and NET have been found to perturb inhibitor affinity (10,11). To explore whether talopram binds within the S2 site in NET, we introduced 32 single-point mutations into 16 different residues within or in close proximity of the S2 site (Fig.…”

Section: Talopram Is Largely Unaffected By Mutations In the Extracellmentioning

confidence: 99%

“…The structures revealed a topology of 12 transmembrane (TM) spanning regions connected by short intra-and extracellular loops with a high-affinity substrate binding site (denoted the S1 site) centrally located in the core of the transporter protein (12). LeuT has proved to be an excellent structural template for construction of homology models of SERT and NET, facilitating identification of the location and molecular structure of binding pockets for substrates, ions, and inhibitors (13)(14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

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

Andersen

Stuhr‐Hansen

Zachariassen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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 structureactivity 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.monoamine | neurotransmitter | SLC6 transporter I mbalances in neurotransmission involving the monoamines serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) are implicated in depression and anxiety disorders (1). In the brain, specific monoamine transporters, the 5-HT transporter (SERT) and the NE transporter (NET), curtail the lifetime of extracellular monoamines by performing active uptake (or reuptake) from the extracellular space into neurons. Medications for the treatment of depression and anxiety disorders act by increasing the extracellular concentration of 5-HT and/or NE by inhibiting SERT and/or NET mediated transmitter reuptake (2). SERT and NET belong to the solute carrier 6 (SLC6) transporter family, and they are integral membrane proteins that use cotransport of sodium as an energy source to convey neurotransmitters from the extracellular space to the cytoplasm (3). The first generation of drugs targeting SERT and NET were the tricyclic antidepressants (TCAs), but their activity across a variety of other neurotransmitter receptor systems (4) associate their use with severe side effects. Development of newer generations of monoamine transporter drugs have focused on compounds with an improved selectivity toward SERT and/or NET, exemplified by the selective 5-HT reuptake inh...

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“…Both models were constructed using the crystal structure of the Aquifex aolicus leucine transporter (LeuT) as a template (Yamashita et al, 2005). The alignment used between LeuT and hSERT and LeuT and hDAT, respectively, was the thoroughly refined one of the neurotransmitter sodium symporters published by Beuming et al (2006) and was previously used by us with success (Celik et al, 2008b;Koldsø et al, 2010Koldsø et al, , 2011Koldsø et al, , 2013aSinning et al, 2010;Severinsen et al, 2012).…”

Section: Molecular Modelingmentioning

confidence: 99%

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

et al. 2013

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Mazindol has been explored as a possible agent in cocaine addiction pharmacotherapy. The tetracyclic compound inhibits both the dopamine transporter and the serotonin transporter, and simple chemical modifications considerably alter target selectivity. Mazindol, therefore, is 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 pharmacologic profiling of rationally chosen serotonin and dopamine transporter mutants with respect to a series of mazindol analogs 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 R-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 versus dopamine transporter Phe155 is found to be a strong tool in tuning the selectivity of mazindol analogs and may be used in future drug design of cocaine abuse pharmacotherapies.

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Binding and Orientation of Tricyclic Antidepressants within the Central Substrate Site of the Human Serotonin Transporter

Cited by 87 publications

References 42 publications

Synthesis and serotonin transporter activity of 1,3-bis(aryl)-2-nitro-1-propenes as a new class of anticancer agents

Synthesis and serotonin transporter activity of 1,3-bis(aryl)-2-nitro-1-propenes as a new class of anticancer agents

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

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

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