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.