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

Piotr Stępnicki; Olga Wronikowska-Denysiuk; Agata Zięba; Katarzyna M Targowska-Duda; Agata Bartyzel; Martyna Z Wróbel; Tomasz M Wróbel; Klaudia Szałaj; Andrzej Chodkowski; Karolina Mirecka; Barbara Budzyńska; Emilia Fornal; Jadwiga Turło; Marián Castro; Agnieszka A Kaczor

doi:10.1080/14756366.2023.2209828

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

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2209828. doi: 10.1080/14756366.2023.2209828.

Authors

Piotr Stępnicki¹, Olga Wronikowska-Denysiuk², Agata Zięba¹, Katarzyna M Targowska-Duda³, Agata Bartyzel⁴, Martyna Z Wróbel⁵, Tomasz M Wróbel¹, Klaudia Szałaj⁶, Andrzej Chodkowski⁵, Karolina Mirecka⁵, Barbara Budzyńska², Emilia Fornal⁶, Jadwiga Turło⁵, Marián Castro^{7

8}, Agnieszka A Kaczor^{1

9}

Affiliations

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.
⁸ Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
⁹ School of Pharmacy, University of Eastern Finland, Kuopio, Finland.

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-HT_1A, and 5-HT_2A 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-HT_1A, and 5-HT_2A receptors on the molecular level. Finally, X-ray study was conducted for compound 1, which revealed its stable conformation in the solid state.

Keywords: Antipsychotic; GPCR; multi-target ligands; schizophrenia.

MeSH terms

Antipsychotic Agents* / chemistry
Antipsychotic Agents* / pharmacology
Dopamine / therapeutic use
Humans
Indazoles
Ligands
Piperazine / pharmacology
Receptor, Serotonin, 5-HT1A / therapeutic use
Receptors, Serotonin
Schizophrenia* / drug therapy
Serotonin / therapeutic use

Substances

Piperazine
Dopamine
Ligands
Indazoles
Serotonin
Receptors, Serotonin
Antipsychotic Agents
Receptor, Serotonin, 5-HT1A

Grants and funding

This work was supported by the National Science Centre (NCN, Poland) under the OPUS Grant 2017/27/B/NZ7/01767 and UMO-2021/43/B/NZ7/01732 (to A.A.K). Calculations were partially performed under a computational grant by Interdisciplinary Centre for Mathematical and Computational Modelling (ICM), Warsaw, Poland, Grant Number G85-948 (to A.A.K.). Molecular modelling was performed under DS33 grant from Medical University of Lublin (to A.A.K). In vitro pharmacology assays were performed with support from the Spanish Ministry of Economy and Competitiveness (MINECO) (Grant Number PID2020-119754GB-I00 to M.C.). The study was also supported in part by an Internal PB Grant for PhD students (Medical University of Lublin, Poland) in terms of in vivo studies, Grant Number PBsd21 (to P.S.). Preliminary synthesis was partially performed with support from the Medical University of Warsaw Student Mini-Grant Number FW26/NM1/16/16. M. C. acknowledges technical assistance from Borja Blanco Babarro, with financial support from European Union-NextGenerationEU (Programa Investigo 2022, XUNTA de Galicia).