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
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
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; Pu, Xiaosui; Umberti, Michelle; Stensbøl, Tine B.; Nielsen, Birgitte; Assaf, Zeinab; Aboab, Bétina; Bolte, Jean; Gefflaut, Thierry; Bunch, Lennart.
In: Journal of Medicinal Chemistry, Vol. 51, No. 14, 2008, p. 4085-4092.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid
T2 - a novel selective inhibitor of human excitatory amino acid transporter subtype 2
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
Y1 - 2008
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
VL - 51
SP - 4085
EP - 4092
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 14
ER -
ID: 5345305