Glutamate-based therapeutic approaches: inhibitors of glycine transport.
A growing body of evidence suggests that activation of the glutamatergic system, particularly N-methyl-D-aspartate (NMDA) receptor function, may be a viable approach to the treatment of schizophrenia, and potentially other cognitive disorders. The excitotoxicity associated with direct NMDA receptor agonists limits their therapeutic potential, and the glycine modulatory site of the NMDA receptor has received growing interest as a therapeutic target. One approach to enhance NMDA receptor function is to increase the availability of the necessary co-agonist glycine at this modulatory site through inhibition of glycine reuptake from the synapse via glycine transporter-1 (GlyT1). Both preclinical and clinical evidence provide support for this approach, as do recent findings demonstrating the regulation of dopaminergic neurotransmission by GlyT1 inhibition. As a result, several groups have focused on the development of novel GlyT1 inhibitors. In addition, recent electrophysiological findings and data from transgenic mouse models suggest that GlyT1 might also play a role in terminating the actions of glycine at strychnine-sensitive glycine receptors, and therefore GlyT1 antagonists also have potential for the treatment of conditions where activation of inhibitory pathways in the central nervous system might be beneficial.
Lechner
Sandra M
SM
Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, CA 92130, USA. slechner@neurocrine.com
D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D002986:Clinical Trials as Topic; D004298:Dopamine / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005998:Glycine / Q000378:metabolism*; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012521:Sarcosine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D009435:Synaptic Transmission
C507205:2-chloro-N-((S)-phenyl((2S)-piperidin-2-yl)methyl)-3-trifluoromethyl benzamide; D001549:Benzamides; D050487:Glycine Plasma Membrane Transport Proteins; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C493271:SLC6A5 protein, human; C493268:SLC6A9 protein, human; D005998:Glycine; D004298:Dopamine; D012521:Sarcosine