TPN672 [7-(2-(4-(benzothiophen-4-yl) piperazin-1-yl)ethyl)quinolin-2(1H)-one maleate] is a novel antipsychotic candidate with high affinity for serotonin and dopamine receptors that is currently in clinical trial for the treatment of psychiatric disorders. In vitro binding study showed that TPN672 exhibited extremely high affinity for serotonin 1A receptor (5-HT1AR) (K i = 0.23 nM) and 5-HT2AR (K i = 2.58 nM) as well as moderate affinity for D3R (K i = 11.55 nM) and D2R (K i = 17.91 nM). In vitro functional assays demonstrated that TPN672 acted as a potent 5-HT1AR agonist, D2R/D3R partial agonist, and 5-HT2AR antagonist. TPN672 displayed robust antipsychotic efficacy in rodent models (e.g., blocking phencyclidine-induced hyperactivity), significantly better than aripiprazole, and ameliorated negative symptoms and cognitive deficits in the sociability test, dark avoidance response, Morris water maze test, and novel object recognition test. The results of electrophysiological experiments showed that TPN672 might inhibit the excitability of the glutamate system through activating 5-HT1AR in medial prefrontal cortex, thereby improving cognitive and negative symptoms. Moreover, the safety margin (the ratio of minimum catalepsy-inducing dose to minimum effective dose) of TPN672 was about 10-fold, which was superior to aripiprazole. In conclusion, TPN672 is a promising new drug candidate for the treatment of schizophrenia and has been shown to be more effective in attenuating negative symptoms and cognitive deficits while having lower risk of extrapyramidal symptoms and hyperprolactinemia. SIGNIFICANCE STATEMENT: TPN672 is a promising new drug candidate for the treatment of schizophrenia and has been shown to be more effective in attenuating negative symptoms and cognitive deficits while having a lower risk of extrapyramidal symptoms and hyperprolactinemia. A phase I clinical trial is now under way to test its tolerance, pharmacokinetics, and pharmacodynamic effects in human volunteers. Accordingly, the present results will have significant impact on the development of new antischizophrenia drugs.
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