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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	51
Udgave nummer	14
Sider (fra-til)	4085-4092
Antal sider	8
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm800091e
Status	Udgivet - 2008

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10.1021/jm800091e

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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.

I: Journal of Medicinal Chemistry, Bind 51, Nr. 14, 2008, s. 4085-4092.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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, bind 51, nr. 14, s. 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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doi = "10.1021/jm800091e",

language = "English",

volume = "51",

pages = "4085--4092",

journal = "Journal of Medicinal Chemistry",

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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

PY - 2008

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N2 - 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.

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.

KW - Cell Line

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

U2 - 10.1021/jm800091e

DO - 10.1021/jm800091e

M3 - Journal article

C2 - 18578477

SN - 0022-2623

VL - 51

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

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ER -

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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