Methylation of l- trans-2,4-Pyrrolidine Dicarboxylate Converts the Glutamate Transport Inhibitor from a Substrate to a Non-substrate Inhibitor

The 4-methyl analogue of the potent inhibitor of CNS l-glutamate neurotransmitter transporters, l- trans-2,4-PDC, was synthesized via a 1,3-dipolar cycloaddition reaction sequence. The bioassays performed not only exhibit increased potency of the methylated derivative over l- trans-2,4-PDC, but also...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2002-11, Vol.10 (11), p.3509-3515
Main Authors: Esslinger, C.Sean, Titus, Jody, Koch, Hans P., Bridges, Richard J., Chamberlin, A.Richard
Format: Article
Language:English
Subjects:
Amino Acid Transport System X-AG - drug effects
Animals
Biological and medical sciences
Carboxylic Acids - chemistry
Computational Biology
Cyclization
Dicarboxylic Acids
Excitatory Amino Acid Transporter 2 - chemistry
Excitatory Amino Acid Transporter 2 - drug effects
Glutamatergic system (aspartate and other excitatory aminoacids)
In Vitro Techniques
Indicators and Reagents
Kinetics
Medical sciences
Methylation
Models, Chemical
Models, Molecular
Molecular Conformation
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Prosencephalon - metabolism
Pyrrolidines - chemistry
Rats
Synaptosomes - drug effects
Synaptosomes - metabolism
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Summary:The 4-methyl analogue of the potent inhibitor of CNS l-glutamate neurotransmitter transporters, l- trans-2,4-PDC, was synthesized via a 1,3-dipolar cycloaddition reaction sequence. The bioassays performed not only exhibit increased potency of the methylated derivative over l- trans-2,4-PDC, but also exhibit non-substrate properties at the rat forebrain synaptosomal glutamate transporter while the parent l- trans-2,4-PDC exhibits substrate properties. These results support two hypotheses developed for distinguishing the physiological properties of transport inhibitors based on molecular modeling studies, and are reported here. Synthesis and evaluation of a potent glutamate neurotransmitter transport inhibitor.
ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(02)00250-X