L-trans-Pyrrolidine-2,4-dicarboxylic Acid

L-trans-Pyrrolidine-2,4-dicarboxylic acid (L-trans-2,4-PDC) is an inhibitor of L-glutamate transport (K_i = 4.6 μM in rat brain synaptosomes).¹ It inhibits radioligand binding to NMDA receptors by 13% but has no effect on AMPA or kainate receptors when used at a concentration of 100 μM. L-trans-2,4-PDC is neurotoxic to astrocyte-rich and astrocyte-poor rat cortical cultures (EC₅₀s = 320 and 50 μM, respectively), an effect that can be reversed by the NMDA antagonist MK-801 (Item No. 10009019) and glutamate-pyruvate transaminase but not the non-NMDA glutamate receptor antagonist CNQX (Item No. 14618).² It induces efflux of the non-metabolizable glutamate analog [³H]-D-aspartate in an extracellular sodium-dependent manner. In vivo, L-trans-2,4-PDC (0.05-0.2 μg/side) prevents amphetamine-induced hyperlocomotion in a dose-dependent manner in rats when injected directly into the nucleus accumbens.³ It also increases bladder intercontraction interval (ICI) without affecting postvoid residual or basal pressure in rats.⁴

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1. Bridges, R.J., Stanley, M.S., Anderson, M.W., et al. Conformationally defined neurotransmitter analogues. Selective inhibition of glutamate uptake by one pyrrolidine-2,4-dicarboxylate diastereomer. J. Med. Chem. 34(2), 717-725 (1991).

2. Blitzblau, R., Gupta, S., Djali, S., et al. The glutamate transport inhibitor L-trans-pyrrolidine-2,4-dicarboxylate indirectly evokes NMDA receptor mediated neurotoxicity in rat cortical cultures. Eur. J. Neurosci. 8(9), 1840-1852 (1996).

3. David, H.N., Thévenoux, A., and Abraini, J.H. Inhibition of the glutamate transporter by L-trans-PDC in the nucleus accumbens prevents the locomotor response to amphetamine. Neuropharmacology 41(3), 409-411 (2001).

4. Honda, M., Yoshimura, N., Hikita, K., et al. Supraspinal and spinal effects of L-trans-PDC, an inhibitor of glutamate transporter, on the micturition reflex in rats. Neurolurol. Urodyn. 32(7), 1026-1030 (2013).