Synthesis and Biological Evaluation of Fiveā€Atomā€Linkerā€Based Arylpiperazine Derivatives with an Atypical Antipsychotic Profile




Chunhui Wu, Yu Wang, Feipu Yang, Wenqiang Shi, Zhen Wang, Ling He, Yang He, Jingshan Shen



Herein we describe a focused set of new arylpiperazine derivatives as potential broadā€spectrum antipsychotics. The general structure contains a quinolinoneā€like moiety, an arylpiperazine moiety, and a fiveā€atom linker. Among them, 7ā€(5ā€(4ā€(benzo[d]isothiazolā€4ā€yl)piperazinā€1ā€yl)pentyl)quinolinā€2(1H)ā€one (S6) shows a promising preclinical profile. CompoundĀ S6, characterized by partial D2R agonism, 5ā€HT1AR agonism, 5ā€HT2AR antagonism, and blockade of SERT activities, was found to decrease psychosisā€ and depressiveā€like symptoms in rodents. The polypharmacological profile ofĀ S6Ā could provide opportunities for the treatment of various other central nervous system disorders such as anxiety, depression, and psychoses associated with dementia. Furthermore,Ā S6Ā demonstrated acceptable safety, toxicology, and pharmacokinetic profiles, and has been selected as a preclinical candidate for further evaluation in schizophrenia.

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