Radomir Juza
PC14 – Radomir Juza
National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic
radomir.juza@nudz.cz
| A novel cariprazine-derived D2/5-HT3 receptor modulators with potential implications for the treatment of schizophrenia and depressive symptoms |
| Radomir Juza¹, Tomas Petrasek¹, Ondrej Soukup², and Jan Korabecny² 1 National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic; 2 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. |
| Abstract Schizophrenia is a serious mental disorder with approximately 1% lifetime prevalence [1]. Currently used antipsychotic drugs are encumbered with many limitations. In addition to frequently occurring side effects [2], in most cases they alleviate predominantly positive symptoms. This effect can be explained by the fact that all registered neuroleptics were primarily discovered to target D2 receptors (D2R) [3]. It has been shown that 5-HT3 receptor (5-HT3R) antagonists, known as setrons, used as add-on treatment to standard antipsychotics, improve clinical symptoms of schizophrenia, especially negative and cognitive symptoms. Furthermore, setrons decrease extrapyramidal side effects of antipsychotics (e.g., tardive dyskinesia) [4]. Another issue observed in schizophrenic patients is the high prevalence of comorbid diseases such as depression. The lifetime prevalence of depression in schizophrenia is reported to be around 40% [5]. Many clinical studies suggest the use of setrons to suppress depressive symptoms [6]. Based on these observations, we present a novel family of D2/5-HT3 receptor ligands combining various arylpiperazine scaffolds and aryl(piperazine-1-yl)methanone moieties tethered by an aliphatic linker, aiming at a comprehensive therapeutic effect in the treatment of schizophrenia and depressive symptoms. This approach merges affinity towards both D2 and 5-HT3 receptors within a single molecular framework. In this contribution, we report the design and synthesis of the compounds in detail, together with their in vitro evaluation, including cytotoxicity assessment, prediction of blood–brain barrier penetration, and determination of affinities and functional activities at the desired receptors. This work was supported by the Czech Science Foundation (project No. 24-11191O). |
| References [1] Stępnicki, P.; Kondej, M.; Kaczor, A.A. Current Concepts and Treatments of Schizophrenia. Molecules 2018, 23, 2087. https://doi.org/10.3390/molecules23082087 [2] De Berardis, D.; et al. Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine. Ther. Adv. Drug Saf. 2018, 9, 237–256. https://doi.org/10.1177/2042098618756261 [3] Karr, S.J.; et al. Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology 2020, 172, 107704. https://doi.org/10.1016/j.neuropharm.2019.107704 [4] Ellenbroek, B.A.; Prinssen, E.P.M. Can 5-HT3 antagonists contribute toward the treatment of schizophrenia? Behav. Pharmacol. 2014, 26, 33–44. https://doi.org/10.1097/FBP.0000000000000102 [5] Ceskova, E. Pharmacological strategies for the management of comorbid depression and schizophrenia. Expert Opin. Pharmacother. 2020, 21, 459–465. https://doi.org/10.1080/14656566.2020.1717466 [6] Bhatt, S.; et al. 5-HT3 Receptor Antagonism: A Potential Therapeutic Approach for the Treatment of Depression and Other Disorders. Curr. Neuropharmacol. 2021, 19, 1545–1559. https://doi.org/10.2174/1570159X18666201015155816 |