Modulation of gamma- aminobutyric acid (GABA) levels by means of neurotransmitter transport inhibition is an established strategy for treating epilepsy. The anticonvulsant  tiagabine is currently the only reuptake inhibitor on the market and is far from being optimal in terms of its side effect profile. In the search for new inhibitor scaffolds, a comparative modeling approach provided a binding mode hypothesis for tiagabine on the GABA transporter 1 (GAT-1). The key features for drug-receptor interaction were used for pharmacophore based virtual screening. Among the compounds meeting the search criteria, also the thyroid hormone liothyronine (T3) was one of the ranked hits. Its activity could subsequently be confirmed by uptake inhibition experiments (IC50 = 12.7 �M). This effect was previously reported for GABA uptake experiments on rat brain synaptosomes, but without concrete information on the binding mode. These findings validate our screening methods, allow the re-purposing of the identified chemical scaffold and provide a starting point for lead optimization of a selective GABA inhibitor. Furthermore, taken together with the known 3D topology of the thyroid hormone receptors, structural differentiation between the fundamentally different systems could be achieved. We acknowledge financial support provided by the Austrian Science Fund, grants F35 and W1232.

From neurotransmitters to hormones and back: Thyroid hormone action on GABA transporters confirmed by virtual screening

248th National Meeting (2014)

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