Discovery of a new class of multi-target heterocycle piperidine derivatives as potential antipsychotics with pro-cognitive effect

https://doi.org/10.1016/j.bmcl.2021.127909Get rights and content

Highlights

  • A series novel benzoisoxazoleylpiperidine derivative was designed and synthesized.

  • Compound 4w shown showed highest affinities to D2, 5-HT1A, 5-HT2A and H3 receptors.

  • Compound 4w has alleviated the schizophrenia-like symptoms and reduced side effects.

  • Compound 4w showed favorable pharmacokinetic profile.

Abstract

A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H3 receptors have been evaluated. Of these compounds, the promising candidate 4w displayed high affinities for D2, D3, 5-HT1A, 5-HT2A and H3, a moderate affinity for 5-HT6, negligible effects on the human ether-a-go-go-related gene (hERG) channel, low affinities for off-target receptors (5-HT2C, adrenergic α1 and H1). In addition, the animal behavioral study revealed that, compared to risperidone, compound 4w significantly inhibited apomorphine-induced climbing and MK-801-induced movement behaviors with a high threshold for catalepsy and low liabilities for weight gain and hyperprolactinemia. Results from the conditioned avoidance response test and novel object recognition task demonstrated that 4w had pro-cognitive effects. Thus, the antipsychotic drug-like activities of 4w indicate that it may be a potential polypharmacological antipsychotic candidate drug.

Graphical abstract

In vitro (Ki, nM): D2, 10.5; D3, 9.6; 5-HT1A, 5.6; 5-HT2A, 8.4; H3, 14.0; 5-HT6, 141.0; H1, 968.3; 5-HT2C, 610.4; α1, 438.2.

In vivo (ED50, mg/Kg): APO, 0.09; MK-801, 0.2; CAT, 32.0; CAR, 1.3.

Pharmacokinetic: t1/2, 5.0 h; F%, 24.0.

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Section snippets

Statistics

In the in vitro binding assays, results were transferred to the program Statistical Package for the program SPSS (Statistical Package for the Social Sciences) for further analysis. In the apomorphine-induced climbing and MK-801-induced hyperactivity test, data were analyzed by the nonparametric two-tailed Mann-Whitney U test. In the conditioned avoidance response test, the statistical analysis was performed by using SPSS software. In the weight gain and serum prolactin test, the statistical

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We are grateful for support Jiangsu Nhwa Pharmaceutical Co., Ltd and the Priority Academic Program Development of Jiangsu Higher Education Institutions of China.

Funding sources

This research was under taken Six Talent Peak project in Jiangsu Province (grant 2019-SWYY-128) and Key research and development program of Lianyungang High-Tech District (ZD201916).

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