The therapeutic potential of glycine transporter-1 inhibitors.
While current antipsychotic medications are often efficacious for the positive symptoms of schizophrenia, there remains a critical need for compounds with improved tolerability and efficacy for the negative symptoms and cognitive dysfunction associated with this disease. There is a growing body of evidence suggesting that the potentiation of N -methyl-D-aspartate (NMDA) receptor function may be a useful approach for the treatment of schizophrenia. One proposed strategy for this potentiation is to increase synaptic levels of the neurotransmitter glycine by blocking the glycine transporter-1. Since glycine acts as a required co-agonist for the NMDA receptor complex; this approach allows an increase in the effectiveness of normal glutamatergic signalling at the NMDA receptor complex. Recent preclinical research, focused on the development and testing of novel glycine transporter-1 inhibitors, suggests that this approach may be feasible. Converging clinical evidence suggesting therapeutic efficacy following the potentiation of glycinergic activity further supports this approach. Clinical studies with novel glycine re-uptake inhibitors will provide critical information regarding the therapeutic utility and tolerability of this treatment for schizophrenia and other disorders associated with NMDA receptor hypofunction.
Sur
Cyrille
C
Department of Neuroscience, Merck Research Laboratories, WP44E-200, West Point, PA 19486, USA.
Kinney
Gene G
GG
D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004358:Drug Therapy / Q000639:trends*; D050487:Glycine Plasma Membrane Transport Proteins; D006801:Humans
D026921:Amino Acid Transport Systems, Neutral; D050487:Glycine Plasma Membrane Transport Proteins; C493268:SLC6A9 protein, human