Development of new photoswitchable azobenzene based γ-aminobutyric acid (GABA) uptake inhibitors with distinctly enhanced potency upon photoactivation.

A series of nipecotic acid derivatives with new azo benzene based photoswitchable N-substituents was synthesized and characterized in their (E)- and (Z)-form for their functional inhibitory activity at gamma aminobutyric acid transporters subtype 1 (GAT1), the most common gamma aminobutyric acid (GABA) transporter subtype in the central nervous system (CNS). This led to the identification of the first photoswitchable ligands exhibiting a moderate uptake inhibition of GABA in their (E)- but distinctive higher inhibitory potency in their (Z)-form resulting from photoirradiation. For the most efficient photoactivatable nipecotic acid derivative displaying an N-but-3-yn-1-yl linker with a terminal diphenyldiazene unit, an inhibitory potency of 4.65 +/- 0.05 (pIC(50)) was found for its (E)-form. which increased by almost two log units up to 6.38 +/- 0.04 when irradiated. The effect of this photoswitchable mGATl inhibitor has also been evaluated and confirmed in patch-clamp recordings in acute hippocampal slices from mice.