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A New Drug Lead for Schizophrenia

A novel third-generation antipsychotic drug lead with the potential to simultaneously treat negative and cognitive symptoms of schizophrenia.

Schizophrenia is a serious mental disorder that affects how people interpret reality. It affects more than 1 per cent of the world’s population and while its causes remain unclear, many of its symptoms can be managed with antipsychotic drugs.

Currently, all on-market antipsychotic drugs treat schizophrenia by targeting dopamine D2 receptors and can be divided into three generations. The most recent third-generation dopamine D2 receptors partial agonist antipsychotics, such as aripiprazole, brexpiprazole, and cariprazine, are effective at relieving positive symptoms of schizophrenia with lowered side effects. However, though these antipsychotic drugs can effectively treat positive symptoms of schizophrenia, no single antipsychotic drug has been developed that can simultaneously treat negative and cognitive symptoms of schizophrenia yet.

Published in Nature Neuroscience, Dr. Wang Sheng’s group from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, in collaboration with Dr. Cheng Jianjun’s group from ShanghaiTech University and Dr. Liu Zhen from the Center of Excellence in Brain Science and Intelligence Technology, report a novel third-generation antipsychotic drug lead with potential antidepressant properties based on structure-guided drug design.

Based on structural analysis of the binding poses of two third-generation antipsychotics, aripiprazole and cariprazine, in 5-HT2AR and DRD2 receptors, the researchers characterised the unique pharmacological properties of the third-generation antipsychotic. From this, they hypothesised that modifying the primary pharmacophore 4-(2,3-dichlorophenyl)piperazine of aripiprazole would disrupt its 5-HT2AR binding without affecting its DRD2 affinity. Based on chemical similarity and molecular size, the aza-ergoline scaffold was selected and when combined with secondary pharmacophores, three third-generation antipsychotic analogues were synthesised with a much bigger aza-ergoline ring. Further analyses of these analogues presented IHCH7041 as the drug lead for additional in vivo pharmacodynamic studies.

Through a variety of tests with mice models, they observed that their drug lead IHCH7041 displayed antipsychotic-like effects and did not induce catalepsy, even at high doses.

Furthermore, as current antipsychotics hardly reduce schizophrenia-related depression and cognitive impairments, IHCH7041 was tested for antidepressant properties and cognition-improving effects via open-field test, forced swim test, tail suspension test, novel object recognition test, and Morris water maze test. When compared with mice in the aripiprazole-administered group, the IHCH7041-administered mice performed better with aripiprazole showing no efficacy in improving negative and cognitive symptoms.

By administering selective antagonists of 5-HT1AR, DRD2, and DRD3 to assess if they were responsible for both antidepressant-like and cognitive effects of IHCH7041, it was observed that 5-HT1AR blocked both these effects.

This work demonstrates a structure-guided drug design campaign that enabled the design of a partial agonist at DRD2/3 and 5-HT1AR with negligible 5-HT2AR binding that outperformed current third-generation antipsychotic drugs in relevant schizophrenia mice models, holding great promise for future clinical application. [APBN]

Source: Chen et al. (2021). Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties. Nature neuroscience, 1-11.