γ‐Aminobutyric Acid and Glycine Neurotransmitter Transporters

This chapter reviews the superfamily 6 of solute carriers (SLC6) subclasses of neurotransmitter transporters that recognize γ-aminobutyric acid (GABA) and Gly, with respect to their neuropharmacology, substrate/inhibitor preferences, structure-activity relationships, and therapeutic potential. A requirement for proper control of receptor activity and hence neuronal excitability is a tight regulation of the amount of extracellular neurotransmitter available. Here, GABA transporters (GATs) and Gly transporters (GLYTs) come into play. The small amino acids GABA and Gly are the major inhibitory neurotransmitters in the mammalian central nervous system (CNS). In terms of structure-function studies, the primary focus until now has been GAT1 and its selective inhibitor tiagabine. While intense efforts to develop bulky 4,4- diphenyl-3-butenyl (DPB)-related compounds were ongoing in the 1990s, the major GABA transporter subtypes were cloned, and it was realized that a majority of the potent lipophilic aromatic inhibitors derived from guvacine and nipecotic acid had a clear preference for GAT1.