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  3. Discovery of novel arylpiperazine-based DA/5-HT modulators as potential antipsychotic agents - Design, synthesis, structural studies and pharmacological profiling

Discovery of novel arylpiperazine-based DA/5-HT modulators as potential antipsychotic agents - Design, synthesis, structural studies and pharmacological profiling

  • Eur J Med Chem. 2023 Apr 5;252:115285. doi: 10.1016/j.ejmech.2023.115285.
Piotr Stępnicki 1,  Katarzyna M Targowska-Duda 2,  Antón L Martínez 3,  Agata Zięba 4,  Olga Wronikowska-Denysiuk 5,  Martyna Z Wróbel 6,  Agata Bartyzel 7,  Alicja Trzpil 8,  Tomasz M Wróbel 4,  Andrzej Chodkowski 6,  Karolina Mirecka 6,  Tadeusz Karcz 9,  Katarzyna Szczepańska 9,  Maria I Loza 3,  Barbara Budzyńska 5,  Jadwiga Turło 6,  Jadwiga Handzlik 9,  Emilia Fornal 8,  Ewa Poleszak 10,  Marián Castro 3,  Agnieszka A Kaczor 11
Affiliations

Affiliations

  • 1 Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093, Lublin, Poland. Electronic address: piotrstepnicki93@gmail.com.
  • 2 Department of Biopharmacy, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093, Lublin, Poland.
  • 3 Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, E-15782, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Travesía da Choupana s/n, E-15706, Santiago de Compostela, Spain.
  • 4 Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093, Lublin, Poland.
  • 5 Independent Laboratory of Behavioral Studies, Biomedical Sciences, Faculty of Biomedicine, Medical University of Lublin, 4A Chodźki St., PL-20093, Lublin, Poland.
  • 6 Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097, Warszawa, Poland.
  • 7 Department of General and Coordination Chemistry and Crystallography, Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie-Sklodowska University in Lublin, Maria Curie-Sklodowska Sq. 2, 20-031, Lublin, Poland.
  • 8 Department of Bioanalytics, Dietetics and Bioanalytics, Faculty of Biomedicine, Medical University of Lublin, Jaczewskiego 8b St., 20-090, Lublin, Poland.
  • 9 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL-30-688, Kraków, Poland.
  • 10 Department of Applied and Social Pharmacy, Faculty of Pharmacy, Medical University of Lublin, 1 Chodźki St., PL-20093, Lublin, Poland.
  • 11 Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093, Lublin, Poland; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. Electronic address: agnieszka.kaczor@umlub.pl.
PMID: 37027998 DOI: 10.1016/j.ejmech.2023.115285
Abstract

Schizophrenia is a mental disorder with a complex pathomechanism involving many neurotransmitter systems. Among the currently used antipsychotics, classical drugs acting as dopamine D2 receptor antagonists, and drugs of a newer generation, the so-called atypical antipsychotics, can be distinguished. The latter are characterized by a multi-target profile of action, affecting, apart from the D2 receptor, also serotonin receptors, in particular 5-HT2A and 5-HT1A. Such profile of action is considered superior in terms of both efficacy in treating symptoms and safety. In the search for new potential antipsychotics of such atypical receptor profile, an attempt was made to optimize the arylpiperazine based virtual hit, D2AAK3, which in previous studies displayed an affinity for D2, 5-HT1A and 5-HT2A receptors, and showed antipsychotic activity in vivo. In this work, we present the design of D2AAK3 derivatives (1-17), their synthesis, and structural and pharmacological evaluation. The obtained compounds show affinities for the receptors of interest and their efficacy as antagonists/agonists towards them was confirmed in functional assays. For the selected compound 11, detailed structural studies were carried out using molecular modeling and X-ray methods. Additionally, ADMET parameters and in vivo antipsychotic activity, as well as influence on memory and anxiety processes were evaluated in mice, which indicated good therapeutic potential and safety profile of the studied compound.

Keywords

Antipsychotic; Arylpiperazine; GPCR; Multi-target compound; Schizophrenia.

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