Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid: a novel selective inhibitor of human excitatory amino acid transporter subtype 2

Emanuelle Sagot; Anders A. Jensen; Darryl S Pickering; Xiaosui Pu; Michelle Umberti; Tine B. Stensbøl; Birgitte Nielsen; Zeinab Assaf; Bétina Aboab; Jean Bolte; Thierry Gefflaut; Lennart Bunch

doi:10.1021/jm800091e

Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid: a novel selective inhibitor of human excitatory amino acid transporter subtype 2

Emanuelle Sagot, Anders A. Jensen, Darryl S Pickering, Xiaosui Pu, Michelle Umberti, Tine B. Stensbøl, Birgitte Nielsen, Zeinab Assaf, Bétina Aboab, Jean Bolte, Thierry Gefflaut, Lennart Bunch

16 Citations (Scopus)

Abstract

In the mammalian central nervous system (CNS), the action of sodium dependent excitatory amino acid transporters (EAATs) is responsible for termination of glutamatergic neurotransmission by reuptake of ( S) -glutamate (Glu) from the synaptic cleft. Five EAAT subtypes have been identified, of which EAAT1-4 are present in the CNS, while EAAT5 is localized exclusively in the retina. In this study, we have used an enantioselective chemo-enzymatic strategy to synthesize 10 new Glu analogues 2a- k ( 2d is exempt) with different functionalities in the 4 R-position and characterized their pharmacological properties at the human EAAT1-3. In particular, one compound, 2k, displayed a significant preference as inhibitor of the EAAT2 subtype over EAAT1,3. The compound also displayed very low affinities toward ionotropic and metabotropic Glu receptors, making it the most selective EAAT2 inhibitor described so far.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	14
Pages (from-to)	4085-4092
Number of pages	8
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm800091e
Publication status	Published - 2008

Keywords

Cell Line
Excitatory Amino Acid Antagonists
Glutamate Plasma Membrane Transport Proteins
Glutarates
Humans
Magnetic Resonance Spectroscopy
Membrane Potentials
Spectrometry, Mass, Electrospray Ionization
Stereoisomerism

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Sagot, E., Jensen, A. A., Pickering, D. S., Pu, X., Umberti, M., Stensbøl, T. B., Nielsen, B., Assaf, Z., Aboab, B., Bolte, J., Gefflaut, T., & Bunch, L. (2008). Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid: a novel selective inhibitor of human excitatory amino acid transporter subtype 2. Journal of Medicinal Chemistry, 51(14), 4085-4092. https://doi.org/10.1021/jm800091e

Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid: a novel selective inhibitor of human excitatory amino acid transporter subtype 2. / Sagot, Emanuelle; Jensen, Anders A.; Pickering, Darryl S et al.
In: Journal of Medicinal Chemistry, Vol. 51, No. 14, 2008, p. 4085-4092.

Research output: Contribution to journal › Journal article › Research › peer-review

Sagot, E, Jensen, AA , Pickering, DS, Pu, X, Umberti, M, Stensbøl, TB, Nielsen, B, Assaf, Z, Aboab, B, Bolte, J, Gefflaut, T & Bunch, L 2008, 'Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid: a novel selective inhibitor of human excitatory amino acid transporter subtype 2', Journal of Medicinal Chemistry, vol. 51, no. 14, pp. 4085-4092. https://doi.org/10.1021/jm800091e

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title = "Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid: a novel selective inhibitor of human excitatory amino acid transporter subtype 2",

abstract = "In the mammalian central nervous system (CNS), the action of sodium dependent excitatory amino acid transporters (EAATs) is responsible for termination of glutamatergic neurotransmission by reuptake of ( S) -glutamate (Glu) from the synaptic cleft. Five EAAT subtypes have been identified, of which EAAT1-4 are present in the CNS, while EAAT5 is localized exclusively in the retina. In this study, we have used an enantioselective chemo-enzymatic strategy to synthesize 10 new Glu analogues 2a- k ( 2d is exempt) with different functionalities in the 4 R-position and characterized their pharmacological properties at the human EAAT1-3. In particular, one compound, 2k, displayed a significant preference as inhibitor of the EAAT2 subtype over EAAT1,3. The compound also displayed very low affinities toward ionotropic and metabotropic Glu receptors, making it the most selective EAAT2 inhibitor described so far.",

keywords = "Cell Line, Excitatory Amino Acid Antagonists, Glutamate Plasma Membrane Transport Proteins, Glutarates, Humans, Magnetic Resonance Spectroscopy, Membrane Potentials, Spectrometry, Mass, Electrospray Ionization, Stereoisomerism",

author = "Emanuelle Sagot and Jensen, {Anders A.} and Pickering, {Darryl S} and Xiaosui Pu and Michelle Umberti and Stensb{\o}l, {Tine B.} and Birgitte Nielsen and Zeinab Assaf and B{\'e}tina Aboab and Jean Bolte and Thierry Gefflaut and Lennart Bunch",

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AU - Sagot, Emanuelle

AU - Jensen, Anders A.

AU - Pickering, Darryl S

AU - Pu, Xiaosui

AU - Umberti, Michelle

AU - Stensbøl, Tine B.

AU - Nielsen, Birgitte

AU - Assaf, Zeinab

AU - Aboab, Bétina

AU - Bolte, Jean

AU - Gefflaut, Thierry

AU - Bunch, Lennart

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AB - In the mammalian central nervous system (CNS), the action of sodium dependent excitatory amino acid transporters (EAATs) is responsible for termination of glutamatergic neurotransmission by reuptake of ( S) -glutamate (Glu) from the synaptic cleft. Five EAAT subtypes have been identified, of which EAAT1-4 are present in the CNS, while EAAT5 is localized exclusively in the retina. In this study, we have used an enantioselective chemo-enzymatic strategy to synthesize 10 new Glu analogues 2a- k ( 2d is exempt) with different functionalities in the 4 R-position and characterized their pharmacological properties at the human EAAT1-3. In particular, one compound, 2k, displayed a significant preference as inhibitor of the EAAT2 subtype over EAAT1,3. The compound also displayed very low affinities toward ionotropic and metabotropic Glu receptors, making it the most selective EAAT2 inhibitor described so far.

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KW - Excitatory Amino Acid Antagonists

KW - Glutamate Plasma Membrane Transport Proteins

KW - Glutarates

KW - Humans

KW - Magnetic Resonance Spectroscopy

KW - Membrane Potentials

KW - Spectrometry, Mass, Electrospray Ionization

KW - Stereoisomerism

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DO - 10.1021/jm800091e

M3 - Journal article

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Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid: a novel selective inhibitor of human excitatory amino acid transporter subtype 2

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Keywords

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