TY - JOUR T1 - TPN672: A Novel Serotonin-Dopamine Activity Modulator for the Treatment of Schizophrenia JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.120.000414 SP - JPET-AR-2020-000414 AU - Yu Wang AU - Yang He AU - Feipu Yang AU - Melkamu Alemu Abame AU - Chunhui Wu AU - Yanmin Peng AU - Linyin Feng AU - Jingshan Shen AU - Zhen Wang AU - Ling He Y1 - 2021/01/01 UR - http://jpet.aspetjournals.org/content/early/2021/05/11/jpet.120.000414.abstract N2 - TPN672,7-(2-(4-(benzo1thiophen-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) (Ki = 0.23 nM) and 5-HT2AR (Ki = 2.58 nM) as well as moderate affinity for D3 receptor (Ki = 11.55 nM) and D2R (Ki = 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, significantly higher than aripiprazole in rodent models (such as blocked phencyclidine-induced hyperactivity , and ameliorated negative symptoms and cognitive deficits in 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 mPFC, 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, 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, meanwhile have lower risk of EPS (Extrapyramidal symptoms) and hyperprolactinemia. Significance Statement TPN672 acted as a potent 5-HT1AR agonist, D2R/D3R partial agonist and 5-HT2AR antagonist, displayed robust antipsychotic efficacy significantly higher than that of aripiprazole in rodent models. 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, meanwhile have a lower risk of EPS (Extrapyramidal symptoms) and hyperprolactinemia. ER -