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

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.

Graphical Abstract

Keywords:

• Antipsychotic
• schizophrenia
• multi-target ligands
• GPCR

Author contributions

P. S.: performed synthesis of the majority of reported compounds, molecular modelling, in vitro and behavioural studies, analysed SAR, and wrote the manuscript; O. W.-D.: performed behavioural studies and wrote the manuscript; A. Z.: performed preliminary synthesis and in vitro studies; K. M. T.-D.: performed and supervised behavioural studies, wrote the manuscript; A. B.: performed X-ray studies and wrote the manuscript; M. Z. W.: performed preliminary synthesis study; T. M. W.: analysed NMR spectra and supervised synthesis; K. S.: performed HPLC analyses; A. C.: performed preliminary synthesis study; K. M. performed preliminary synthesis study; B. B.: performed and supervised behavioural studies; E. F.: supervised HPLC analyses; J. T.: supervised synthesis; M. C.: supervised and analysed in vitro studies, acquired funding, and wrote the manuscript; A. A. K.: designed the study, supervised molecular modelling and acquired funding. All authors also read and revised the manuscript.

Disclosure statement

The authors report there are no competing interests to declare.

Data availability statement

The data that support the findings of this study are available in the Supplementary Information of this article.

Additional information

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).