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  • Pyrrolidinedithiocarbamate ammonium Finally it is possible t


    Finally, it is possible that the increase in the number of EAAT-3-labelled cells in the DG at PD 60, when compared with the control and experimental animals at PD 14, is associated with natural changes in the number of neurons present during the postnatal development of the hippocampus (41, 42) and, to a lesser extent, to the changes induced by MSG evident in cells labeled for GAT-1. Moderate immunoreactivity to GAT-1 has been found around the stratum pyramidale and granular layer between PD 5 and PD 30 (14), and after PD 45, the subgranular region is the area most densely stained, in conjunction with the punctuate staining of the pyramidal and granular cell layers between the nonexpressing cell bodies. This temporal gradient of GAT-1 expression during development in untreated rats correlates well with our results.
    Acknowledgments This research was supported by grants COECYTJAL–University of Guadalajara (PS-2009-489 and 558) and CONACYT-SEP-CB 106179. We wish to thank Dr. Sonia Luquín de Anda for assistance with the fluorescence microscopy.
    It is widely believed that the dysfunction of glutamate transmission participates in the etiology of a number of neurodegenerative and neuropsychiatric disorders and diseases. In the mammalian central nervous system, the excitatory amino Pyrrolidinedithiocarbamate ammonium transporter (EAAT) family of proteins is responsible for the high-affinity sodium-dependent uptake of glutamate into both astroglial cells and neurons. Normal EAAT function is required both for the efficient termination of glutamatergic neurotransmission and clearance of glutamate from the synaptic cleft, thereby preventing excitotoxicity. Among the five recently identified subtypes of excitatory aminoacid transporters (EAAT-1–5), three of them (EAAT-1/GLAST, EAAT-2/GLT-1, and EAAT-3/EAAC1) are involved in synaptic glutamate homeostasis. Further classification distinguishes neuronal transporter EAAT-3 from glial Pyrrolidinedithiocarbamate ammonium transporters EAAT-1 and EAAT-2, with the latter being the major contributor to glutamate uptake from the synapse. An ever-growing interest in the area led to the discovery of several classes of restricted glutamate analogs as inhibitors of EAATs (pyrolidine dicarboxylates, aminocyclobutane dicarboxylates, and carboxycyclopropyl glycines). Many of these relatively compact molecules act as competitive (transportable) substrates inducing transport currents and heteroexchange. A close structural similarity of these earlier series with glutamate presents a plausible explanation for the poor selectivity across EAAT subtypes and substantial affinity to other glutamate receptors (mGluRs and iGluRs). Finally, their use as pharmacological tools is also affected by modest micromolar potency and poor physico-chemical properties. While more recently designed non-transportable ligands, such as dl--β-hydroxyaspartate and its benzylated derivative (TBOA), and the novel heptane dicarboxylate-3-amino-tricyclo[]heptane-1,3-dicarboxylic acid offered improved potency, they still fall short of being ideal tool molecules. The latest generation of TBOA-based analogs delivers nanomolar potent EAAT-2 inhibitors (measured in transfected MDCK cells), with the most selective agent PMB-TBOA ((2,3(S)-3-[3-(4-methoxybenzoylamino)benzyloxy]aspartate) exhibiting a 39-fold selectivity over EAAT3. Manifesting a notably better profile, this series still leaves room for improvement in selectivity and physico-chemical properties. In this study, we present the synthesis and structure–activity studies of a structurally distinct series possessing high potency and selectivity in HEK cell lines together with a potentially promising overall biopharmacological profile. Focusing on creating sufficient structural dissimilarity with glutamate and improvement of pharmacological characteristics, we constructed variable lipophilic structural fragments with the terminal carboxy- and amino-groups of aspartic and 2,3-diaminopropionic acid correspondingly. In comparison with TBOA series, these inhibitors possess only one chiral center and a free carboxylic acid group, potentially simplifying the syntheses and improving physico-chemical properties.