Journal
CHEMMEDCHEM
Volume 14, Issue 24, Pages 2042-2051Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201900439
Keywords
D-2; 5-HT1A; 5-HT2A; serotonin; SERT; PCP-induced hyperactivity
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Funding
- Special Foundation of Chinese Academy of Sciences for strategic pilot technology [XDA12040105]
- Youth Program of National Natural Science Foundation of China [81703338]
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China [2018ZX09711002]
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Herein we describe a focused set of new arylpiperazine derivatives as potential broad-spectrum antipsychotics. The general structure contains a quinolinone-like moiety, an arylpiperazine moiety, and a five-atom linker. Among them, 7-(5-(4-(benzo[d]isothiazol-4-yl)piperazin-1-yl)pentyl)quinolin-2(1H)-one (S6) shows a promising preclinical profile. Compound S6, characterized by partial D2R agonism, 5-HT1AR agonism, 5-HT2AR antagonism, and blockade of SERT activities, was found to decrease psychosis- and depressive-like symptoms in rodents. The polypharmacological profile of S6 could provide opportunities for the treatment of various other central nervous system disorders such as anxiety, depression, and psychoses associated with dementia. Furthermore, S6 demonstrated acceptable safety, toxicology, and pharmacokinetic profiles, and has been selected as a preclinical candidate for further evaluation in schizophrenia.
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