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Screening for novel modulators of GABAA receptors

University of British Columbia

GABAA receptors are a family of ligand gated ion channels that play essential roles both in normal brain functions and psychiatric conditions. While the classical GABAA receptor modulators benzodiazepines have been in clinical use for decades and are still among the most widely prescribed drugs for the treatment of certain disorders, their limitations and side effects have been driving the search for alternative solutions. Recent studies from our lab have demonstrated that glutamate can act as positive allosteric modulators of GABAA receptors, and the suggested binding sites are on the interface of alpha and beta subunits. This surprising finding drove us to pursuit two objectives: (1) screen glutamate-like molecules that can compete with glutamate and prevent the potentiation of GABAA receptors, so we can study the intrinsic functions of the modulating effects of glutamate; (2) screen glutamate-like molecules that can mimic glutamate and potentiate GABAA receptors but do not produce any other physiological effects, so we can utilize them as candidates for clinical treatment as alternatives of benzodiazepines. Experiments are performed on hippocampal neuron cultures and HEK 293 cells transfected with GABAA receptor subunits. Virtual screening and electrophysiology recording are employed. For objective (1), we identified 10 compounds that can inhibit glutamate from potentiating GABAA receptor. Unfortunately, none of them can completely block the potentiation. For objective (2), we identified one compound, 2-methyl aspartic acid (2-MAA), as the final candidate for further study. We found that 2-MAA shares the binding sites with glutamate and potentiates GABAA receptors in a dose-dependent manner, while it does not affect normal neuronal activities. In addition, although it shows no significant effect on tonic GABA current amplitude, it does increase the frequency of mini-IPSCs. In the future, for objective (1), it will require screening for additional candidates and/or modification of the 10 compounds. For objective (2), we can continue testing the anti-epilepsy effect of 2-MAA on both in vitro and in vivo models. It will also be applicable to modify the compound or to screen similar compounds so as to get a better candidate with bigger potentiation at a lower concentration.

Text

2013-10-07

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/45215

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/