Concise Asymmetric Synthesis and Pharmacological Characterization of All Stereoisomers of Glutamate Transporter Inhibitor TFB-TBOA and Synthesis of EAAT Photoaffinity Probes

Leuenberger, Michele; Ritler, Andreas; Simonin, Alexandre; Hediger, Matthias; Lochner, Martin (2016). Concise Asymmetric Synthesis and Pharmacological Characterization of All Stereoisomers of Glutamate Transporter Inhibitor TFB-TBOA and Synthesis of EAAT Photoaffinity Probes. ACS chemical neuroscience, 7(5), pp. 534-539. American Chemical Society 10.1021/acschemneuro.5b00311

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Glutamate is the major excitatory neurotransmitter in the mammalian brain. Its rapid clearance after the release into the synaptic cleft is vital in order to avoid toxic effects and is ensured by several transmembrane transport proteins, so-called excitatory amino acid transporters (EAATs). Impairment of glutamate removal has been linked to several neurodegenerative diseases and EAATs have therefore received increased attention as therapeutic targets. O-benzylated L-threo-β-hydroxyaspartate derivatives have been developed previously as highly potent inhibitors of EAATs with TFB-TBOA ((2S,3S)-2-amino-3-((3-(4-(trifluoromethyl)benzamido)benzyl)oxy)succinic acid) standing out as low-nanomolar inhibitor. We report the stereoselective synthesis of all four stereoisomers of TFB-TBOA in less than a fifth of synthetic steps than the published route. For the first time, the inhibitory activity and isoform selectivity of these TFB-TBOA enantio- and diastereomers were assessed on human glutamate transporters EAAT1-3. Furthermore, we synthesized potent photoaffinity probes based on TFB-TBOA using our novel synthetic strategy.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Leuenberger, Michele; Ritler, Andreas; Simonin, Alexandre; Hediger, Matthias and Lochner, Martin

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry
600 Technology > 610 Medicine & health

ISSN:

1948-7193

Publisher:

American Chemical Society

Funders:

[4] Swiss National Science Foundation
[65] NCCR TransCure

Language:

English

Submitter:

Martin Lochner

Date Deposited:

06 Apr 2016 10:28

Last Modified:

27 Feb 2017 02:30

Publisher DOI:

10.1021/acschemneuro.5b00311

PubMed ID:

26918289

BORIS DOI:

10.7892/boris.79285

URI:

https://boris.unibe.ch/id/eprint/79285

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