Glyt1 Inhibitor Design, Synthesis And Activity

Objective:Schizophrenia is a psychiatric disorders, which is characterized by a combination of negative (social withdrawal, blunting of emotional responses, anhedonia) and positive (hallucinations, delusions, paranoia, disorganized behavior) symptoms along with significant cognitive dysfunction. It is the most serious form of mental illness. In recent years, it can be found that the schizophrenia is making a great impact on the people's life and work. Therefore it is important to design and synthesize a class of safe and effective drug for treatment of schizophrenia.In recent years, the NMDA hypothesis is widely accepted, which holds the concept that schizophrenia due to the hypofunction of NMDA receptor. Clinical studies have shown that increasing the levels of glycine near the NMDA receptor in brain can help alleviate the negative and cognitive behavioral symptoms. The glycine level of the synaptic cleft is controlled by the glycine transporter (GlyT1) in presynaptic membrane. The quantity of glycine can be increased if the glycine transporter is inhibited in the synaptic cleft, and thus it can enhance the activity of NMDA receptors. Therefore, the development of glycine transporter inhibitors for the treatment of schizophrenia is of great significance, GlyTl inhibitor research and development also represents a new generation of antipsychotic drugs.Method:By literature surveying, we noticed that Merck's compounds ACPPB had excellent activity (IC50<10nM), and the relatively new structure type. Therefore, consulting the basic skeleton of Merck, considering the hydrogen bonds of the structure in vivo, we designed and synthesized a series of quinazolinone compounds (ZA1-ZA12) via the typical chemical reaction process (consideration, applications alkylation, reduction, sulfonation) and tested them inhibitory activity of the cells in vitro. We hope that some express excellent inhibitory activity.Result:The results showed that at 10μmol/L tested concentration, relative to the positive compounds ZAO, the compounds ZA2, ZA8 and ZA11 express the more than 70% inhibitory rate, and that of ZA4 is only 9%.Conclusion:The results of our research showed that the inhibitory activities of some compounds were better compared with the positive compound, but there is a gap. We expected to get some safe and effective compounds through further structural optimization.