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 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.
Esslinger
C
C
COBRE Center For Structural and Functional Neuroscience, Department of Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA. seaness@selway.umt.edu
Titus
Jody
J
Koch
Hans
H
Bridges
Richard
R
Chamberlin
A
A
D027322:Amino Acid Transport System X-AG / Q000187:drug effects*; D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry*; D019295:Computational Biology; D003500:Cyclization; D003998:Dicarboxylic Acids; D027342:Excitatory Amino Acid Transporter 2 / Q000737:chemistry / Q000187:drug effects; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007700:Kinetics; D008745:Methylation; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D016548:Prosencephalon / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry*; D051381:Rats; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D027322:Amino Acid Transport System X-AG; D002264:Carboxylic Acids; D003998:Dicarboxylic Acids; D027342:Excitatory Amino Acid Transporter 2; D007202:Indicators and Reagents; D011759:Pyrrolidines; C083486:pyrrolidine-2,4-dicarboxylic acid