Binding of the Amphetamine-like 1-Phenyl-piperazine to Monoamine Transporters

Severinsen, Kasper; Kraft, Johan F.; Koldsø, Heidi; Vinberg, Katrine A; Rothman, Richard B.; Partilla, John S.; Wiborg, Ove; Blough, Bruce E.; Schiøtt, Birgit; Sinning, Steffen

doi:10.1021/cn300040f

Cited by 27 publications

(41 citation statements)

References 44 publications

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“…The possible ionic interaction between the charged N1 position of mazindol and Asp98 in hSERT and Asp78 in hDAT is the dominant docking poses of both enantiomers in both proteins. This type of charge-reinforced interaction was previously seen in other compounds that interact with hSERT (Celik et al, 2008b;Koldsø et al, 2010Koldsø et al, , 2011Koldsø et al, , 2013aSinning et al, 2010), hDAT (Beuming et al, 2008), or both (Severinsen et al, 2012;Koldsø et al, 2013b) and the presence of a protonated ammonium group is a hallmark of high-affinity inhibitors of SERT and DAT.…”

Section: Resultssupporting

confidence: 62%

“…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%

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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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Section: Resultssupporting

confidence: 62%

Section: Molecular Modelingmentioning

confidence: 99%

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

et al. 2013

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“…6, in which the theoretical space for a releaser is in the center, and structural expansion in any direction eventually converts the compound to an uptake inhibitor. Detailed molecular modeling of substrate activity at the DAT and SERT has been carried out using phenylpiperazine and phenethylamine analogs which are releasing substrates (Severinsen et al, 2012; Seddik et al, 2013). Other models are currently being developed.…”

Section: Atypical Releasersmentioning

confidence: 99%

Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter

Reith

Blough

Hong

et al. 2015

Drug and Alcohol Dependence

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Background Treatment of Stimulant-Use Disorders remains a formidable challenge, and the dopamine transporter (DAT) remains a potential target for antagonist or agonist-like substitution therapies. Methods This review focuses on DAT ligands, such as benztropine, GBR 12909, modafinil, and DAT substrates derived from phenethylamine or cathinone that have atypical DAT-inhibitor effects, either in vitro or in vivo. The compounds are described from a molecular mechanistic, behavioral, and medicinal-chemical perspective. Results Possible mechanisms for atypicality at the molecular level can be deduced from the conformational cycle for substrate translocation. For each conformation, a crystal structure of a bacterial homolog is available, with a possible role of cholesterol, which is also present in the crystal of drosophila DAT. Although there is a direct relationship between behavioral potencies of most DAT inhibitors and their DAT affinities, a number of compounds bind to the DAT and inhibit dopamine uptake but do not share cocaine-like effects. Such atypical behavior, depending on the compound, may be related to slow DAT association, combined sigma-receptor actions, or bias for cytosol-facing DAT. Some structures are sterically small enough to serve as DAT substrates but large enough to also inhibit transport. Such compounds may display partial DA releasing effects, and may be combined with release or uptake inhibition at other monoamine transporters. Conclusions Mechanisms of atypical DAT inhibitors may serve as targets for the development of treatments for stimulant abuse. These mechanisms are novel and their further exploration may produce compounds with unique therapeutic potential as treatments for stimulant abuse.

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“…Structural information of SERT and NET is still lacking, but X-ray crystal structures of the bacterial homolog LeuT (Yamashita et al, 2005;Krishnamurthy and Gouaux, 2012) have proved to be excellent structural templates for its mammalian counterparts and facilitated identification of the location and structure of ligand-binding sites in human transporters (Beuming et al, 2008;Celik et al, 2008;Andersen et al, 2009Andersen et al, , 2010Kaufmann et al, 2009;Koldsø et al, 2010Koldsø et al, , 2013aSinning et al, 2010;Plenge et al, 2012;Severinsen et al, 2012Severinsen et al, , 2013. Structures of LeuT have also provided direct insight into the binding mechanism of antidepressants.…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis for Selective Serotonin Reuptake Inhibition by the Antidepressant Agent Fluoxetine (Prozac)

et al. 2014

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Inhibitors of the serotonin transporter (SERT) are widely used antidepressant agents, but the structural mechanism for inhibitory activity and selectivity over the closely related norepinephrine transporter (NET) is not well understood. Here we use a combination of chemical, biological, and computational methods to decipher the molecular basis for high-affinity recognition in SERT and selectivity over NET for the prototypical antidepressant drug fluoxetine (Prozac; Eli Lilly, Indianapolis, IN). We show that fluoxetine binds within the central substrate site of human SERT, in agreement with recent X-ray crystal structures of LeuBAT, an engineered monoamine-like version of the bacterial amino acid transporter LeuT. However, the binding orientation of fluoxetine is reversed in our experimentally supported model compared with the LeuBAT structures, emphasizing the need for careful experimental verification when extrapolating findings from crystal structures of bacterial transporters to human relatives. We find that the selectivity of fluoxetine and nisoxetine, a NET selective structural congener of fluoxetine, is controlled by residues in different regions of the transporters, indicating a complex mechanism for selective recognition of structurally similar compounds in SERT and NET. Our findings add important new information on the molecular basis for SERT/NET selectivity of antidepressants, and provide the first assessment of the potential of LeuBAT as a model system for antidepressant binding in human transporters, which is essential for future structure-based drug development of antidepressant drugs with fine-tuned transporter selectivity.

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Binding of the Amphetamine-like 1-Phenyl-piperazine to Monoamine Transporters

Cited by 27 publications

References 44 publications

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

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

Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter

Molecular Basis for Selective Serotonin Reuptake Inhibition by the Antidepressant Agent Fluoxetine (Prozac)

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