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Continuation of structure–activity relationship study of novel benzamide derivatives as potential antipsychotics
Author(s) -
Xu Mingshuo,
Guo Shuang,
Yang Feipu,
Wang Yu,
Wu Chunhui,
Jiang Xiangrui,
Zhao Qingjie,
Chen Weiming,
Tian Guanghui,
Zhu Fuqiang,
Xie Yuanchao,
Hu Tianwen,
Wang Zhen,
He Yang,
Shen Jingshan
Publication year - 2019
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201800306
Subject(s) - benzamide , phencyclidine , chemistry , catalepsy , pharmacology , serotonin , in vivo , receptor , 5 ht receptor , potency , pharmacophore , stereochemistry , dopamine , in vitro , haloperidol , nmda receptor , medicine , biochemistry , biology , microbiology and biotechnology
A series of benzamide derivatives possessing potent dopamine D 2 , serotonin 5‐HT 1A , and 5‐HT 2A receptor properties were synthesized and evaluated as potential antipsychotics. Among them, 5‐(4‐(4‐(benzo[ d ]isothiazol‐3‐yl)piperazin‐1‐yl)butoxy)‐ N ‐cyclopropyl‐2‐fluorobenzamide ( 4k ) held the best pharmacological profile. It not only exhibited potent and balanced activities for the D 2 , 5‐HT 1A , and 5‐HT 2A receptors, but was also endowed with low to moderate activities for the 5‐HT 2C , H 1 , and M 3 receptors, suggesting a low propensity for inducing weight gain or diabetes. In animal models, compound 4k reduced phencyclidine‐induced hyperactivity with a high threshold for catalepsy or muscle relaxation induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, 4k was selected as a candidate for further development.