Continuation of structure-activity relationship study of novel benzamide derivatives as potential antipsychotics.

Abstract

A series of benzamide derivatives possessing potent dopamine D2 , serotonin 5-HT1A , and 5-HT2A 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 D2 , 5-HT1A , and 5-HT2A receptors, but was also endowed with low to moderate activities for the 5-HT2C , H1 , and M3 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.

• Authors: Mingshuo Xu, Shuang Guo, Feipu Yang, Yu Wang, Chunhui Wu, Xiangrui Jiang, Qingjie Zhao, Weiming Chen, Guanghui Tian, Fuqiang Zhu, Yuanchao Xie, Tianwen Hu, Zhen Wang, Yang He, Jingshan Shen
• Journal: Archiv der Pharmazie (Arch Pharm (Weinheim)) Vol. 352 Issue 4 Pg. e1800306 (Apr 2019) ISSN: 1521-4184 [Electronic] Germany
• PMID: 30702760 (Publication Type: Journal Article)
• Copyright: © 2019 Deutsche Pharmazeutische Gesellschaft.

Chemical References

• Antipsychotic Agents
• Benzamides
• Receptor, Serotonin, 5-HT2A
• Receptors, Dopamine D2
• Receptor, Serotonin, 5-HT1A
• Phencyclidine

Topics

• Animals
• Antipsychotic Agents (chemical synthesis, chemistry, pharmacology)
• Behavior, Animal (drug effects)
• Benzamides (chemical synthesis, chemistry, pharmacology)
• Disease Models, Animal
• Humans
• Male
• Mice
• Mice, Inbred ICR
• Motor Activity (drug effects)
• Phencyclidine (toxicity)
• Receptor, Serotonin, 5-HT1A (drug effects, metabolism)
• Receptor, Serotonin, 5-HT2A (drug effects, metabolism)
• Receptors, Dopamine D2 (drug effects, metabolism)
• Schizophrenia (drug therapy, physiopathology)
• Structure-Activity Relationship