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Chemoenzymatic Synthesis and Pharmacological Characterization of Functionalized Aspartate Analogues As Novel Excitatory Amino Acid Transporter Inhibitors. 2018

Haigen Fu, and Jielin Zhang, and Pieter G Tepper, and Lennart Bunch, and Anders A Jensen, and Gerrit J Poelarends
Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy , University of Groningen , Antonius Deusinglaan 1 , 9713 AV Groningen , The Netherlands.

Aspartate (Asp) derivatives are privileged compounds for investigating the roles governed by excitatory amino acid transporters (EAATs) in glutamatergic neurotransmission. Here, we report the synthesis of various Asp derivatives with (cyclo)alkyloxy and (hetero)aryloxy substituents at C-3. Their pharmacological properties were characterized at the EAAT1-4 subtypes. The l- threo-3-substituted Asp derivatives 13a-e and 13g-k were nonsubstrate inhibitors, exhibiting pan activity at EAAT1-4 with IC50 values ranging from 0.49 to 15 μM. Comparisons between (dl- threo)-19a-c and (dl- erythro)-19a-c Asp analogues confirmed that the threo configuration is crucial for the EAAT1-4 inhibitory activities. Analogues (3b-e) of l-TFB-TBOA (3a) were shown to be potent EAAT1-4 inhibitors, with IC50 values ranging from 5 to 530 nM. Hybridization of the nonselective EAAT inhibitor l-TBOA with EAAT2-selective inhibitor WAY-213613 or EAAT3-preferring inhibitor NBI-59159 yielded compounds 8 and 9, respectively, which were nonselective EAAT inhibitors displaying considerably lower IC50 values at EAAT1-4 (11-140 nM) than those displayed by the respective parent molecules.

UI MeSH Term Description Entries
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000642 Ammonia-Lyases Enzymes that catalyze the formation of a carbon-carbon double bond by the elimination of AMMONIA. EC 4.3.1. Ammonia Lyase,Ammonia-Lyase,Ammonia Lyases,Lyase, Ammonia
D001224 Aspartic Acid One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. (+-)-Aspartic Acid,(R,S)-Aspartic Acid,Ammonium Aspartate,Aspartate,Aspartate Magnesium Hydrochloride,Aspartic Acid, Ammonium Salt,Aspartic Acid, Calcium Salt,Aspartic Acid, Dipotassium Salt,Aspartic Acid, Disodium Salt,Aspartic Acid, Hydrobromide,Aspartic Acid, Hydrochloride,Aspartic Acid, Magnesium (1:1) Salt, Hydrochloride, Trihydrate,Aspartic Acid, Magnesium (2:1) Salt,Aspartic Acid, Magnesium-Potassium (2:1:2) Salt,Aspartic Acid, Monopotassium Salt,Aspartic Acid, Monosodium Salt,Aspartic Acid, Potassium Salt,Aspartic Acid, Sodium Salt,Calcium Aspartate,Dipotassium Aspartate,Disodium Aspartate,L-Aspartate,L-Aspartic Acid,Magnesiocard,Magnesium Aspartate,Mg-5-Longoral,Monopotassium Aspartate,Monosodium Aspartate,Potassium Aspartate,Sodium Aspartate,Aspartate, Ammonium,Aspartate, Calcium,Aspartate, Dipotassium,Aspartate, Disodium,Aspartate, Magnesium,Aspartate, Monopotassium,Aspartate, Monosodium,Aspartate, Potassium,Aspartate, Sodium,L Aspartate,L Aspartic Acid
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D050491 Glutamate Plasma Membrane Transport Proteins A family of plasma membrane neurotransmitter transporter proteins that couple the uptake of GLUTAMATE with the import of SODIUM ions and PROTONS and the export of POTASSIUM ions. In the CENTRAL NERVOUS SYSTEM they regulate neurotransmission through synaptic reuptake of the excitatory neurotransmitter glutamate. Outside the central nervous system they function as signal mediators and regulators of glutamate metabolism. Neurotransmitter Transport Proteins, Glutamate-Specific,Neurotransmitter Transporters, Glutamate-Specific,EAAT Proteins,Excitatory Amino Acid Transport Proteins,Excitatory Amino Acid Transporter Proteins,Glutamate Plasma Membrane Transporter Proteins,Sodium-Glutamate Cotransporter,Sodium-Glutamate Transporter,Cotransporter, Sodium-Glutamate,Glutamate-Specific Neurotransmitter Transporters,Neurotransmitter Transport Proteins, Glutamate Specific,Neurotransmitter Transporters, Glutamate Specific,Sodium Glutamate Cotransporter,Sodium Glutamate Transporter,Transporters, Glutamate-Specific Neurotransmitter
D050580 Excitatory Amino Acid Transporter 3 A neuronal and epithelial type glutamate plasma membrane transporter protein. EAAC-1 Excitatory Amino-Acid Carrier,EAAT-3 Excitatory Amino Acid Transporter,SLC1A1 Transporter,EAAC 1 Excitatory Amino Acid Carrier,EAAT 3 Excitatory Amino Acid Transporter,Transporter, SLC1A1
D050581 Excitatory Amino Acid Transporter 4 A glutamate plasma membrane transporter protein that is primarily expressed in cerebellar PURKINJE CELLS on postsynaptic DENDRITIC SPINES. EAAT-4 Excitatory Amino Acid Transporter,SLC1A6 Transporter,EAAT 4 Excitatory Amino Acid Transporter,Transporter, SLC1A6
D057809 HEK293 Cells A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5. 293T Cells,HEK 293 Cell Line,HEK 293 Cells,Human Embryonic Kidney Cell Line 293,Human Kidney Cell Line 293,293 Cell, HEK,293 Cells, HEK,293T Cell,Cell, 293T,Cell, HEK 293,Cell, HEK293,Cells, 293T,Cells, HEK 293,Cells, HEK293,HEK 293 Cell,HEK293 Cell
D027341 Excitatory Amino Acid Transporter 1 A glial type glutamate plasma membrane transporter protein found predominately in ASTROCYTES. It is also expressed in HEART and SKELETAL MUSCLE and in the PLACENTA. EAAT-1 Excitatory Amino Acid Transporter,GLAST-1 Glutamate Aspartate Transporter,Glutamate Aspartate Transporter 1,SLC1A3 Transporter,EAAT 1 Excitatory Amino Acid Transporter,GLAST 1 Glutamate Aspartate Transporter,Transporter, SLC1A3

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