In a study published in Nature Neuroscience, Dr. WANG Sheng's team from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences (CAS), collaborating with Dr. CHENG Jianjun’s team from ShanghaiTech University and Dr. LIU Zhen from the Center for Excellence in Brain Science and Intelligence Technology of CAS, reported a novel third-generation antipsychotic drug lead with potential antidepressant properties based on structure-guided drug design. They conducted a complete preclinical drug development pipeline starting from deciphering the drug-on-target structures to the in vivo validating the efficacy of third-generation antipsychotic drug lead in relevant schizophrenia-mimic rodent models.
Currently, all on-market antipsychotics treat schizophrenia via targeting dopamine D2 receptors. According to their R&D history and pharmacological characteristics, antipsychotics can be divided into three generations. The first-generation antipsychotics (FGAs) represented by haloperidol function as potent antagonists of dopamine D2 receptor (DRD2), while the second-generation antipsychotics (SGAs) behave as antagonists at both DRD2 and serotonin (5-hydrotryptamine, 5-HT) receptor 2A (5-HT2AR). Severe extrapyramidal symptoms (EPS) brought in by FGAs and metabolic side effects aroused by SGAs raised the drug safety concerns and hindered their long-term usage. Third-generation antipsychotics (TGAs), i.e., aripiprazole, brexpiprazole, and cariprazine, act as partial agonists of DRD2, which, together with their low occupancy on DRD2, lowered their side-effect liability.
Despite all antipsychotics can effectively treat positive symptoms of schizophrenia, no single antipsychotic can simultaneously treat negative and cognitive symptoms pertaining to schizophrenia yet.
Based on structural analysis of the binding poses of two TGAs, aripiprazole and cariprazine, in two major receptor targets, 5-HT2AR and DRD2, the researchers characterized the unique pharmacological properties of TGAs and designed a novel drug lead via modifying the primary pharmacophore 4-(2,3-dichlorophenyl)piperazine of cariprazine into a bulkier aza-ergoline ring, which results in the TGA lead, IHCH7041.
As the shrinkage of the binding pocket of 5-HT2AR that accommodate the primary pharmacophore of TGAs, the enlarged aza-ergoline ring of IHCH7041 precludes its binding to 5-HT2AR. Affinity and pharmacological profiling of IHCH7041 to common targets in central nervous system showed that IHCH7041 only binds to DRD2, DRD3, and 5-HT1AR with high affinity and acts as partial agonist at the three receptors. The "clean" and defined target profile of IHCH7041 predicted low side-effect liability. Indeed, IHCH7041, even at a very high-dose (10 mg/kg), induces no catalepsy.
Furthermore, the researchers validated the antipsychotic efficacy, antidepressant potential, and cognition-improving efficacy via open-field test, forced swim test, tail suspension test, novel object recognition test, and Morris water maze test. Mice in IHCH7041-administered group outperformed mice in aripiprazole-administered group, while aripiprazole showed no efficacy in improving negative and cognitive symptoms. By using selective antagonists of the three receptors to block in vivo efficacies of IHCH7041, they identified that 5-HT1AR is the on-target responsible for both the antidepressant potential and the cognition-improving efficacy of IHCH7041.
This work showcases a structure-guided drug design campaign which produces a novel third-generation antipsychotic drug lead with a "cleaner" target profile. This drug lead outperformed extant TGAs in relevant schizophrenia mouse models and holds great promise for future clinical application.