Glycine transporter 1 inhibitors and modulation of NMDA receptor-mediated excitatory neurotransmission.
In the central nervous system, glutamate is essential for a proper synaptic communication in neuronal networks supporting critical behavioral activities such as learning and memory. Dysfunction of glutamatergic excitatory neurotransmission has been implicated in numerous neurological and pyschiatric disorders and a growing body of research suggests that potentiation of NMDA receptor function may represent a novel approach for the treatment of schizophrenia. An actively pursued strategy to potentiate NMDA receptor function is to increase synaptic levels of the neurotransmitter glycine by blocking the glycine transporter type 1 (GlyT1). Since glycine acts as a co-agonist at the NMDA receptor, this approach could enhance the effectiveness of normal NMDA receptor-mediated glutamatergic neurotransmission. Recent research on the physiology of this uptake system as well as on the development and preclinical testing of novel GlyT1 inhibitors have greatly enhanced our knowledge of the role of this transporter in the modulation of NMDA receptor activity and suggested that this approach may be feasible. Clinical studies with novel glycine reuptake inhibitors will provide critical information regarding the validity of this therapeutic concept for the treatment of schizophrenia and other disorders associated with NMDA receptor hypofunction.
Sur
Cyrille
C
Department of Imaging and Neuroscience Drug Discovery, Merck Research Laboratories, West Point, PA 19486, USA. cyrille_sur@merck.com
Kinney
Gene G
GG
D000595:Amino Acid Sequence; D000818:Animals; D018683:Excitatory Amino Acid Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology*
D018683:Excitatory Amino Acid Agents; D050487:Glycine Plasma Membrane Transport Proteins; D016194:Receptors, N-Methyl-D-Aspartate