Synthesis and pharmacological evaluation of piperidine (piperazine)-amide substituted derivatives as multi-target antipsychotics

doi:10.1016/j.bmcl.2020.127506

Bioorganic & Medicinal Chemistry Letters

Volume 30, Issue 20, 15 October 2020, 127506

https://doi.org/10.1016/j.bmcl.2020.127506 Get rights and content

Highlights

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A series novel multi-target piperidine (piperazine)-amide substituted derivatives was designed and synthesized.
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Compound 11 shown potent and selective in vitro activities on D₂, 5-HT_1A, 5-HT_2A, 5- HT₆, 5-HT_2c, α₁ and α₂ receptors.
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Compound 11 has obvious effect on alleviating the schizophrenia-like symptoms and exhibited pro-cognitive capabilities in animal model.
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Compound 11 showed favorable pharmacokinetic profile.

Abstract

We report the optimisation of a series of novel amide-piperidine (piperazine) derivatives using the multiple ligand approach with dopamine and serotonin receptors. Of the derivatives, compound 11 exhibited high affinity for the D₂, 5-HT_1A, and 5-HT_2A receptors, but low affinity for the 5-HT_2C and histamine H₁ receptors and human ether-a-go-go-related gene (hERG) channels. In vivo, compound 11 reduced apomorphine-induced climbing, MK-801-induced hyperactivity and DOI-induced head twitching without observable catalepsy, even at the highest dose tested. In addition, it exhibited suppression in a CAR test. Furthermore, in a novel object recognition task, it displayed procognition properties. Therefore, compound 11 is a promising candidate multi-target antipsychotic.

Graphical abstract

In vitro (K_i, nM): D_2, 2.1; 5-HT_1A, 3.5; 5-HT_2A, 7.8; 5-HT₆, 12.9; 5-HT_2c, 1987; H₁, 2134; α₁, 3296. In vivo (ED₅₀, mg/kg): APO, 0.28; DOI, 0.22; MK-801, 0.19; CAT, 25.2; CAR, 0.28. Pharmacokinetic: t_1/2, 3.34h; F, 31.04%.

Section snippets

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 financial support from the Six Talent Peak project in Jiangsu Province (grant 2019-SWYY-128). We are grateful for support the Priority Academic Program Development of Jiangsu Higher Education Institutions of China.

Financial disclosure

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.

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^d: Ling Huang and Lanchang Gao contributed equally to this work.

View full text

Synthesis and pharmacological evaluation of piperidine (piperazine)-amide substituted derivatives as multi-target antipsychotics

Highlights

Abstract

Graphical abstract

Section snippets

Declaration of Competing Interest

Acknowledgements

Financial disclosure

Pharmacol Biochem Behav

Biol Psychiatry

Brain Res

Neurobiol Learn Mem

Eur J Med Chem

Behav Brain Res

Neuropharmacology

J Pharmacol Toxicol Methods

Neurochem Int

Pharmacol Biochem Behav

Behav Brain Res

Eur J Med Chem

Eur J Med Chem

History of the concept of disconnectivity in schizophrenia

Harv Rev Psychiatry

Haloperidol-induced catalepsy is mediated by postsynaptic dopamine receptors

Nature

Medication continuation and compliance: a comparison of patients treated with clozapine and haloperidol

J Clin Psychiatry

Risperidone versus haloperidol in the treatment of chronic schizophrenic inpatients: a multicentre double-blind comparative study

Acta Psychiatr Scand

Tarsy, Dopamine and the pathophysiology of dyskinesias induced by antipsychotic drugs

Rev Neurosci

The history of clozapine

Psychopharmacology

Drug treatment of schizophrenia. Overview of recent research

Schizophr Res

Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis

BMJ

Add-on aripiprazole for atypical antipsychotic-induced, clinically significant hyperprolactinemia

Indian J Psychol Med

Metformin treatment of antipsychotic-induced dyslipidemia: an analysis of two randomized, placebo-controlled trials

Mol Psychiatry

Impact of histamine receptors H1 and H3 polymorphisms on antipsychotic-induced weight gain

World J Biol Psychia

Impact of histamine receptors H₁ and H₃ polymorphisms on antipsychotic-induced weight gain