科研之友
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摘要
Schizophrenia is a devastating psychiatric disorder affecting 1% of the population worldwide. Typical and atypical antipsychotic agents, which are currently used for the treatment of this disease, preferably influence positive symptoms but exhibit only limited effects on the negative symptoms of this mental disorder. Neurochemical studies indicate that typical antipsychotics predominantly alter schizophrenic symptoms by blockade of dopamine D-2 receptors, whereas atypical antipsychotics influence schizophrenic symptoms by blockade of both dopamine D-2 and serotonin 5-HT2A receptors, besides the involvement of effects on additional receptors. The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyper-functional dopaminergic and glutamatergic neurotransmission in the central nervous system. The latter hypothesis is based upon decreased activity of N-methyl-D-aspartate (NMDA) receptors particularly in the prefrontal cortex. Hypofunctional NMDA receptors are now believed to be responsible primarily for the negative symptoms and cognitive deficits in schizophrenia. Hypofunctional NMDA receptors can be reactivated by glycine transporter 1 (GlyT-1) inhibitors, which inhibit glycine reuptake, increase synaptic glycine concentrations, and thus indirectly activate glycine(B) binding sites at the NR1 subunit of NMDA receptors. The discovery of drug-like GlyT-1 inhibitors may be a major breakthrough in the treatment of schizophrenia. It is assumed that drugs increasing glutamatergic tone by inhibition of synaptic reuptake of glycine may be more suitable for therapeutic influence of the positive and negative symptoms, as well as the cognitive deficit in schizophrenia, when added to conventional antipsychotics. At present, bitopertin and Org-25935 are the two most advanced drugs possessing this mechanism of action and they are expected to be introduced in human therapy in the following years.
- 出版日期2013-8
