TPN672: A Novel Serotonin-Dopamine Receptor Modulator for the Treatment of Schizophrenia

doi:10.1124/jpet.120.000414

	TPN672: A Novel Serotonin-Dopamine Receptor Modulator for the Treatment of Schizophrenia
	Wang, Yu 1,2; He, Yang 2; Yang, Feipu 2; Abame, Melkamu Alemu 2; Wu, Chunhui 3; Peng, Yanmin 4; Feng, Linyin 2; Shen, Jingshan 2; Wang, Zhen 2; He, Ling 1
刊名	JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
	2021-07-01
卷号	378 期号:1 页码:20-30
ISSN号	0022-3565
DOI	10.1124/jpet.120.000414
通讯作者	Wang, Zhen(wangzhen@simm.ac.cn) ; He, Ling(heling92@hotmail.com)
英文摘要	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-HT1(AR) agonist, D2R/D3R partial agonist, and 5-HT2AR antagonist. TPN672 displayed robust antipsychotic efficacy in rodent models (e.g., blocking phencyclidineinduced 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.
资助项目	National Natural Science Foundation of China[81673434] ; Double First-Class University plan[CPU2018GY22] ; Special Foundation of Chinese Academy of Sciences for strategic pilot technology[XDA12040105] ; Special Foundation of Chinese Academy of Sciences for strategic pilot technology[XDA12040337] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002] ; Science and Technology Commission of Shanghai Municipality[17431900500]
WOS关键词	ANTIPSYCHOTIC-LIKE ; 5-HT1A RECEPTORS ; OBJECT RECOGNITION ; SELECTIVE BLOCKADE ; CLINICAL-FEATURES ; KEY ROLE ; D-3 ; DRUG ; RATS ; COGNITION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000686414700003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297996]
专题	中国科学院上海药物研究所
通讯作者	Wang, Zhen; He, Ling
作者单位	1.China Pharmaceut Univ, Dept Pharmacol, 24 Tong Jia Xiang, Nanjing 210009, Jiangsu, Peoples R China 2.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China 3.Topharman Shanghai Co Ltd, Dept Pharmacol, Shanghai, Peoples R China 4.Shanghai Jiao Tong Univ, Shanghai Mental Hlth Ctr, Sch Med, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Wang, Yu,He, Yang,Yang, Feipu,et al. TPN672: A Novel Serotonin-Dopamine Receptor Modulator for the Treatment of Schizophrenia[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,2021,378(1):20-30.
APA	Wang, Yu.,He, Yang.,Yang, Feipu.,Abame, Melkamu Alemu.,Wu, Chunhui.,...&He, Ling.(2021).TPN672: A Novel Serotonin-Dopamine Receptor Modulator for the Treatment of Schizophrenia.JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,378(1),20-30.
MLA	Wang, Yu,et al."TPN672: A Novel Serotonin-Dopamine Receptor Modulator for the Treatment of Schizophrenia".JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 378.1(2021):20-30.