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.
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.
Sagot
Emanuelle
E
Departement de Chimie, Universite Blaise Pascal, 63177 Aubiere Cedex, France.
Jensen
Anders A
AA
Pickering
Darryl S
DS
Pu
Xiaosui
X
Umberti
Michelle
M
Stensbøl
Tine B
TB
Nielsen
Birgitte
B
Assaf
Zeinab
Z
Aboab
Bétina
B
Bolte
Jean
J
Gefflaut
Thierry
T
Bunch
Lennart
L
D002460:Cell Line; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D005977:Glutarates / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008564:Membrane Potentials / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism
C530997:2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid; D018691:Excitatory Amino Acid Antagonists; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; D005977:Glutarates; C493397:SLC1A2 protein, human