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 γ-aminobutyric acid transporters
subtype 1 (GAT1), the most common γ-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 (pIC50) 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 mGAT1
inhibitor has also been evaluated and confirmed in patch-clamp recordings
in acute hippocampal slices from mice.