Inhibition of glycine transporter 1: The yellow brick road to new schizophrenia therapy?

Abstract

While pharmacological blockade of dopamine D2 receptor can effectively suppress the psychotic or positive symptoms of schizophrenia, there is no satisfactory medication for the negative and cognitive symptoms of schizophrenia in spite of the proliferation of second generation antipsychotic drugs. Excitements over a new class of third generation antipsychotics that might possibly fill this urgent medical need have been prompted by the recent development of glycine transporter 1 (GlyT1) inhibitors. The impetus of this novel pharmacological strategy stems directly from the prevailing hypothesis that negative and cognitive symptoms are attributable to the hypofunction of glutamatergic signalling via the N-methyl-D-aspartate (NMDA) receptor in the brain. Inhibition of GlyT1 reduces clearance of extra-cellular glycine near NMDA receptor-containing synapses, and thereby increases baseline occupancy of the glycine-B site at the NR1 subunit of the NMDA receptor, which is a prerequisite of channel activation upon stimulation by the excitatory neurotransmitter glutamate. Pharmacological inhibition of GlyT1 is expected to boost NMDA receptor function and therefore alleviate persistent negative and cognitive symptoms without excessive risk of excitotoxicity associated with direct NMDA receptor agonists. The recently completed phase III clinical trials of the Roche compound, bitopertin (a.k.a. RG1678 or RO-4917838) had initially raised hope that this new class of drugs might represent the first successful translation of the glutamate hypothesis of schizophrenia to the clinic. However, the outcomes of the multi-centre bitopertin clinical trials have been disappointing. The present review seeks to examine this promise through a critical survey of the latest clinical and preclinical findings on the therapeutic potential of GlyT1 inhibition or down-regulation.

• Authors: Philipp Singer, Sylvain Dubroqua, Benjamin K Yee
• Journal: Current pharmaceutical design (Curr Pharm Des) Vol. 21 Issue 26 Pg. 3771-87 ( 2015) ISSN: 1873-4286 [Electronic] United Arab Emirates
• PMID: 26205290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antipsychotic Agents
• Glycine Plasma Membrane Transport Proteins
• Neurotransmitter Agents
• Receptors, N-Methyl-D-Aspartate
• Glycine

Topics

• Animals
• Antipsychotic Agents (pharmacology, therapeutic use)
• Brain (drug effects, physiopathology)
• Drug Discovery
• Glycine (physiology)
• Glycine Plasma Membrane Transport Proteins (antagonists & inhibitors, physiology)
• Humans
• Neurotransmitter Agents (physiology)
• Receptors, N-Methyl-D-Aspartate (drug effects, physiology)
• Schizophrenia (drug therapy, physiopathology)
• Synapses (drug effects, physiology)