Novel GABA Transporter GAT Inhibitors

The clinical use of tiagabine as an AED has established GAT-1 as a bona fide anticonvulsant drug target.38,51 An extensive structure-activity relationship study has been established around this AED52 leading to newer GAT-1 inhibitors including exo-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (exo-THPO) and Lu-32-176B (Figure 4).53 EF1502 (Figure 4) is a N-substituted analog of THPO that inhibits both mouse GAT-1 and GAT-2 in transfected cell lines had synergistic rather than additive anticonvulsant effects in combination with exo-THPO in the rat PTZ-seizure model and the Frings audiogenic seizure-susceptible mouse. This effect occurred without synergistically impairing rotorod performance suggesting that the human form of mouse GAT-2 might be a novel AED target. GAT can also facilitate GABA release by reversing in response to depolarization, an effect that is enhanced by gabapentin and vigabatrin. Modulation of GAT reverse transport may thus be a physiological source of GABA during seizures.54

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