As the primary excitatory transmitter in the mammalian CNS, L-glutamate participates in fast excitatory signaling, as well as the higher order processing required in development, plasticity, learning and memory. The pervasiveness of this system in the normal functioning of the CNS is equally matched by its association with a wide variety of neurological disorders, including acute stroke, chronic neurodegenerative diseases, epilepsy, depression, Parkinson's disease, and schizophrenia. Whether for the purposes of elucidating normal signaling mechanisms, pathological processes, or novel therapeutic strategies, investigations aimed at modulating this system have most often focused at the level of glutamate receptors. Recent work has identified a potentially novel mechanism through which glutamate-mediated excitatory transmission may be regulated at the level of glutamate release. While delineating the pharmacological specificity of the transporter responsible for loading L-glutamate into synaptic vesicles, it was found that this system appears to be potently inhibited by select steroids. This suggests that these compounds might play a role in determining the amount of L-glutamate present in synaptic vesicles and, consequently, the quantity actually released during excitatory transmission. If such a mechanism exists, it represents a non-genomic pathway through which steroids may regulate one of the most prominent transmitter systems in the CNS. Importantly, it also identifies a novel therapeutic site that could be exploited to correct imbalances in the glutamate systems that may underlie several debilitating neurological disorders. As much as identifying a new regulatory mechanism for excitatory transmission would represent a substantial breakthrough, the potential importance of this mechanism must be tempered by what is not known. Thus, the goal of the proposed experiments is to address fundamental issues related to specificity and potency of action, which must first be explored before the full relevance of this novel modulatory mechanism can be either appreciated or systematically investigated on a larger scale. It is for these reasons that we believe the R21 program represents the most appropriate grant mechanism.
| Carrigan, Christina N; Patel, Sarjubhai A; Cox, Holly D et al. (2014) The development of benzo- and naphtho-fused quinoline-2,4-dicarboxylic acids as vesicular glutamate transporter (VGLUT) inhibitors reveals a possible role for neuroactive steroids. Bioorg Med Chem Lett 24:850-4 |
| Ahmed, S Kaleem; Etoga, Jean-Louis G; Patel, Sarjubhai A et al. (2011) Use of the hydantoin isostere to produce inhibitors showing selectivity toward the vesicular glutamate transporter versus the obligate exchange transporter system x(c)(-). Bioorg Med Chem Lett 21:4358-62 |
| Etoga, Jean-Louis G; Ahmed, S Kaleem; Patel, Sarjubhai et al. (2010) Conformationally-restricted amino acid analogues bearing a distal sulfonic acid show selective inhibition of system x(c)(-) over the vesicular glutamate transporter. Bioorg Med Chem Lett 20:2680-3 |
| Thompson, Charles M; Davis, Erin; Carrigan, Christina N et al. (2005) Inhibitor of the glutamate vesicular transporter (VGLUT). Curr Med Chem 12:2041-56 |
