Discovery of a new class of multi-target heterocycle piperidine derivatives as potential antipsychotics with pro-cognitive effect
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.
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).
References (39)
- et al.
Complexity and schizophrenia
Prog Nueuro-Psychoph
(2013) - et al.
Synthesis and evaluation of new coumarin derivatives as potential atypical antipsychotics
Eur J Med Chem
(2014) - et al.
5-HT6 receptor and cognition
Curr Opin Pharmacol
(2011) - et al.
Distribution of the histaminergic neuron system in the central nervous system of rats; a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker
Brain Res
(1984) - et al.
Role of serotonin 5-HT2C and histamine H1 receptors in antipsychotic-induced diabetes: a pharmacoepidemiological-pharmacodynamic study in VigiBase
Eur Neuropsychopharm
(2015) - et al.
Evidence that conditioned avoidance responses are reinforced by positive prediction errors signaled by tonic striatal dopamine
Behav Brain Res
(2013) - et al.
Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat
Behav Brain Res
(2007) - et al.
Synthesis and biological evaluation of a series of multi-target N-substituted cyclic imide derivatives with potential antipsychotic effect
Eur J Med Chem
(2018) - et al.
Effects of antipsychotic drugs on neurites relevant to schizophrenia treatment
Med Res Rev
(2019) - et al.
Classics in chemical neuroscience: clozapine
ACS Chem Neurosci
(2013)
Classics in chemical neuroscience: risperidone
ACS Chem Neurosci
Multi-target approach for drug discovery against schizophrenia
Int J Mol Sci
Pharmacological treatment of schizophrenia - a review -of progress
Prog. Neuro-Psych
Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia
CNS Drugs
Comparative tolerability of dopamine D2/3 receptor partial agonists for schizophrenia
CNS Drugs
Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism
CNS Drugs
5-HT1A receptor, an old target for new therapeutic agents
Curr Top Med Chem
Improving the treatment of schizophrenia: role of 5-HT receptors in modulating cognitive and extrapyramidal motor functions
CNS Neurol Disord: Drug Targets
Targeting serotonin 5-HT2A receptors to better treat schizophrenia: rationale and current approaches
CNS Drugs
Cited by (3)
Novel chiral Schiff base Palladium(II), Nickel(II), Copper(II) and Iron(II) complexes: Synthesis, characterization, anticancer activity and molecular docking studies
2022, Bioorganic ChemistryCitation Excerpt :Cisplatin was employed as a reference drug in this study. Additionally, we studied the intermolecular interactions established between the more active complex, L1-Pd(II), and the targets including colon cancer and breast cancer proteins, encoded 2HQ6 and 2AR9, respectively with the aid of the molecular docking perspective [28,29], which was validated using control compound, cisplatin. All reagents and the chemicals were purchased from Sigma-Aldrich, Merck, and Fluka companies.
Robust and predictive QSAR models for predicting the D<inf>2</inf>, 5-HT<inf>1A</inf>, and 5-HT<inf>2A</inf> inhibition activities of fused tricyclic heterocycle piperazine (piperidine) derivatives as atypical antipsychotic drugs
2022, Journal of Molecular StructureCitation Excerpt :In 2021, Gao et al. had designed heterocycle piperazine (piperidine) derivatives with Ki values at nano-molar level against the D2, 5-HT1A, 5-HT2A and human histamine H3 receptors. Few piperidine derivatives in their research showed higher affinities to D2, 5-HT1A, and 5-HT2A receptors with respect to risperidone and aripiprazole [20,21]. These researches show that piperazine (piperidine) derivatives can be considered as potential antipsychotics by targeting the D2, 5-HT1A, 5-HT2A receptors and the presence of a mathematical model for predicting their receptor affinity against these receptors are helpful in designing new antipsychotics with greater activates.