GlyT1 (SLC6A9) inhibition in neurological and psychiatric disorders

Abstract

Glycine is a fundamental neuroactive amino acid that serves dual roles in the central nervous system: acting as a primary inhibitory neurotransmitter via strychnine-sensitive glycine receptors and as an essential co-agonist at the N-methyl-Daspartate (NMDA) receptor. This dual functionality is important for maintaining the excitation–inhibition balance, synaptic plasticity, and network stability. The spatial and temporal availability of glycine is strictly regulated by two high-affinity, Na+/Cl−-dependent transporters: GlyT1 (SLC6A9) and GlyT2 (SLC6A5). These transporters exhibit distinct cellular distributions and functional specializations. GlyT1 is predominantly expressed in astrocytes and specific neuronal populations, where it buffers ambient glycine levels to modulate NMDA receptor activity. In contrast, GlyT2 is primarily localized to presynaptic terminals of glycinergic neurons, where it facilitates vesicular refilling essential for inhibitory signaling. This review provides a comprehensive overview of glycine metabolism, the structural biology and transport cycles of SLC6 glycine transporters, and the neuroanatomical framework of GlyT1 function. We further synthesize pharmacological advances in GlyT1 inhibition, evaluating both sarcosine-derived and non-sarcosine inhibitors, such as NFPS (ALX-5407), bitopertin, and iclepertin. The clinical and preclinical evidence for GlyT1 as a therapeutic target in psychiatric, neurological, and neurodegenerative disorders is critically assessed. Finally, we address key translational challenges, including dosing constraints, compensatory mechanisms, and SLC6 family selectivity, while highlighting the potential of structure-guided design to refine GlyT1-targeted therapies.