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Scientists elucidate the role of GlyT1 in anti-schizophrenia drugs
Schizophrenia is a highly disabling mental disorder, and numerous studies have shown that the hypofunction of the N-methyl-d-aspartate (NMDA) receptor is one of its pathogenic mechanisms. Glycine transporter 1 (GlyT1), a glycine transporter protein, is highly co-localized with the NMDA receptor. Inhibition of GlyT1 can increase the concentration of glycine in the synaptic cleft, thereby indirectly promoting NMDA receptor activation. Therefore, GlyT1 is considered a key target for the treatment of schizophrenia.
sodium ions that were co-transported with glycine, elucidating the coupling mechanism of substrate and ion binding during transport.
Currently, clinical candidate drugs targeting GlyT1 for the treatment of schizophrenia can be divided into sarcosine-based and non-sarcosine-based classes. The researchers found that the initial lead sarcosine-based inhibitor, ALX-5407, binds to an inward pocket of GlyT1.
They also identified the first patented non-sarcosine-based inhibitor SSR504734, and the drug PF-03463275, which is currently in Phase II clinical trials, to bind to an outward pocket of GlyT1.
This study explores the substrate recognition, ion binding, conformational transition of GlyT1, and the structure-activity relationships with the clinical trial drugs. The researchers believe it will help accelerate the drug development process targeting GlyT1, providing strong theoretical support for the design and development of anti-schizophrenia drugs.
More information: Yiqing Wei et al, Transport mechanism and pharmacology of the human GlyT1, Cell (2024).
Journal information: Cell
Provided by Chinese Academy of Sciences
