Structure–Activity Relationship and Pharmacology of γ‐Aminobutyric Acid (GABA) Transport Inhibitors

This chapter describes the structure–activity relationship and pharmacology of γ‐aminobutyric acid (GABA) transport inhibitors. The group of GABA uptake inhibitors includes competitive substrate‐related GABA analogs of low‐molecular weight displaying variance in pharmacological profile and inhibitors based on these substrate‐related inhibitors but modified with lipophilic aromatic side chains. The latter display competitive, mixed type, and noncompetitive inhibition kinetics and are often highly GAT1 selective. While much is known about the inhibition of the cloned GABA transporter GAT1 because of the existence of selective, potent, and blood–brain barrier penetrating GAT1 inhibitors, little is known about the role and therapeutic potential of the other transporter subtypes. Despite extensive variation in the lipophilic aromatic part of these inhibitors there continues to be a need for potent and selective inhibitors of other transporter subtypes. However, compounds targeting GAT2/BGT‐1 have recently appeared and in vivo administration of such compounds has pointed to an important role of this transporter subtype in seizure control. The inhibition kinetics could affect the nature of GABA uptake intervention.