Discovery of 4-benzoylpiperidine and 3-(piperidin-4-yl)benzo[d]isoxazole derivatives as potential and selective GlyT1 inhibitors

Yang Liu, Lin Guo, Hongliang Duan, Liming Zhang, Neng Jiang, Xuechu Zhen, Jianhua Shen

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Regulation of glycine transporter 1 (GlyT1) activity is a currently investigated strategy in drug discovery for schizophrenia. This study developed a series of new 4-benzoylpiperidine derivatives as GlyT1 inhibitors by bioisosteric replacement and mimicking of the pyridine ring of RG1678. Among the 4-benzoylpiperidine derivatives, 23q showed an IC50 of 30 nM. Preliminary optimization of the blood-brain barrier penetration led to the discovery of 3-(piperidin-4-yl)benzo[d]isoxazole derivatives. Both series showed good selectivity over GlyT2, D1, D2, D3, 5-HT1A and 5-HT2A receptors. Moreover, behavioral testing showed 23q (40 mg kg-1, intragastric) can inhibit the hyperlocomotion induced by acute treatment of phencyclidine, and improve the impaired negative and cognitive symptoms in chronic phencyclidine-induced C57BL/6J mice. An interesting finding showed that 3-(piperidin-4-yl)benzo[d]isoxazole was a privileged scaffold of atypical antipsychotic agents but exhibited high selectivity and potency as a GlyT1 inhibitor.

Original languageEnglish
Pages (from-to)40964-40977
Number of pages14
JournalRSC Advances
Volume5
Issue number51
DOIs
Publication statusPublished - 2015
Externally publishedYes

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