Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 145, Issue -, Pages 74-85Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.12.099
Keywords
Antipsychotic; Cyclic imide; Multi-target; 5-HT1A receptor
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Funding
- Special Foundation of Chinese Academy of Sciences for strategic pilot technology [XDA12040208]
- R&D Program of Shanghai Municipal Science and Technology Commission [14431905500]
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In the present study, a series of multi-target N-substituted cyclic imide derivatives which possessed potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties were synthesized and evaluated as potential antipsychotics. Among these compounds, (3aR,4R,7S,7aS)-2-(4-(4-(benzo[b]thiophen-4-yl) piperazin-1-yl)butyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione hydrochloride (3d) held a promising pharmacological profile. 3d not only showed potent and balanced in vitro activities on D-2/5-HT1A/5-HT2A receptors, but also endowed with low to moderate activities on 5-HT2c, H-1,H- alpha(1A), M-3 receptors and hERG channel, suggesting a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In animal behavioral studies, 3d reduced phencyclidine induced hyperlocomotion with a high threshold for catalepsy induction. Compound 3d was selected as a potential antipsychotic candidate for further development. (C) 2018 Elsevier Masson SAS. All rights reserved.
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