Abstract

Abstract

Schizophrenia is a chronic mental disorder that is not satisfactorily treated with available antipsychotics. The presented study focuses on the search for new antipsychotics by optimising the compound D2AAK3, a multi-target ligand of G-protein-coupled receptors (GPCRs), in particular D2, 5-HT1A, and 5-HT2A receptors. Such receptor profile may be beneficial for the treatment of schizophrenia. Compounds 1–16 were designed, synthesised, and subjected to further evaluation. Their affinities for the above-mentioned receptors were assessed in radioligand binding assays and efficacy towards them in functional assays. Compounds 1 and 10, selected based on their receptor profile, were subjected to in vivo tests to evaluate their antipsychotic activity, and effect on memory and anxiety processes. Molecular modelling was performed to investigate the interactions of the studied compounds with D2, 5-HT1A, and 5-HT2A receptors on the molecular level. Finally, X-ray study was conducted for compound 1, which revealed its stable conformation in the solid state.

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Title
Novel multi-target ligands of dopamine and serotonin receptors for the treatment of schizophrenia based on indazole and piperazine scaffolds–synthesis, biological activity, and structural evaluation
Author
Stępnicki, Piotr 1 ; Wronikowska-Denysiuk, Olga 2 ; Zięba, Agata 1 ; Targowska-Duda, Katarzyna M 3 ; Bartyzel, Agata 4 ; Wróbel, Martyna Z 5 ; Wróbel, Tomasz M 1 ; Szałaj, Klaudia 6 ; Chodkowski, Andrzej 5 ; Mirecka, Karolina 5 ; Budzyńska, Barbara 2 ; Fornal, Emilia 6 ; Turło, Jadwiga 5 ; Castro, Marián 7 ; Kaczor, Agnieszka A 8 

1  Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy, Medical University of Lublin , Lublin , Poland 
2  Independent Laboratory of Behavioral Studies, Chair of Biomedical Sciences, Faculty of Biomedicine, Medical University of Lublin , Lublin , Poland 
3  Department of Biopharmacy, Faculty of Pharmacy, Medical University of Lublin , Lublin , Poland 
4  Department of General and Coordination Chemistry and Crystallography, Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie-Sklodowska University in Lublin , Lublin , Poland 
5  Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw , Warsaw , Poland 
6  Department of Bioanalytics, Faculty of Biomedicine, Medical University of Lublin , Lublin , Poland 
7  Department of Pharmacology, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela , Santiago de Compostela , Spain, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS) , Santiago de Compostela , Spain 
8  Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy, Medical University of Lublin , Lublin , Poland, School of Pharmacy, University of Eastern Finland , Kuopio , Finland 
Publication year
2023
Publication date
Dec 2023
Publisher
Taylor & Francis Ltd.
ISSN
14756366
e-ISSN
14756374
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1080/14756366.2023.2209828
ProQuest document ID
2917549178
Copyright
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.. This work is licensed under the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.