Description
L-trans-Pyrrolidine-2,4-dicarboxylic acid (L-trans-2,4-PDC) is an inhibitor of L-glutamate transport (Ki = 4.6 μM in rat brain synaptosomes). 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 and glutamate-pyruvate transaminase but not the non-NMDA glutamate receptor antagonist CNQX. 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. It also increases bladder intercontraction interval (ICI) without affecting postvoid residual or basal pressure in rats.
Biological Activity
Potent, competitive, transportable EAAT1-4 inhibitor/non-transportable EAAT5 inhibitor. Also available as part of the Excitatory Amino Acid Transporter Inhibitor Tocriset™ .
References
[1] RICHARD J. BRIDGES. Conformationally defined neurotransmitter analogs. Selective inhibition of glutamate uptake by one pyrrolidine-2,4-dicarboxylate diastereomer[J]. Journal of Medicinal Chemistry, 1991, 34 2: 717-725. DOI:
10.1021/jm00106a037.
[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] MASASHI HONDA. Supraspinal and spinal effects of L-trans-PDC, an inhibitor of glutamate transporter, on the micturition reflex in rats.[J]. Neurourology and Urodynamics, 2013, 32 7: 1026-1030. DOI:
10.1002/nau.22351.
