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

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