2. Academic Validation
  3. Novel D2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment

Novel D2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment

  • Eur J Med Chem. 2022 Mar 15:232:114193. doi: 10.1016/j.ejmech.2022.114193.
Radomir Juza 1,  Iveta Vojtechova 2,  Kristyna Stefkova-Mazochova 2,  Wim Dehaen 3,  Tomas Petrasek 2,  Lukas Prchal 4,  Tereza Kobrlova 4,  Jiri Janousek 4,  Premysl Vlcek 2,  Eva Mezeiova 5,  Daniel Svozil 3,  Jana Zdarova Karasova 6,  Jaroslav Pejchal 6,  Holger Stark 7,  Grzegorz Satala 8,  Andrzej J Bojarski 8,  Monika Kubacka 9,  Szczepan Mogilski 9,  Alena Randakova 10,  Kamil Musilek 11,  Ondrej Soukup 12,  Jan Korabecny 13
Affiliations

Affiliations

  • 1 National Institute of Mental Health, Topolova 748, Klecany, 250 67, Czech Republic; University of Hradec Kralove, Department of Chemistry, Hradecka 1285, 500 01, Hradec Kralove, Czech Republic.
  • 2 National Institute of Mental Health, Topolova 748, Klecany, 250 67, Czech Republic.
  • 3 Department of Informatics and Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology Prague, Technicka 5, 166 28, Prague, Czech Republic.
  • 4 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
  • 5 National Institute of Mental Health, Topolova 748, Klecany, 250 67, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
  • 6 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
  • 7 Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, D-40225 Duesseldorf, Germany.
  • 8 Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Krakow, Poland.
  • 9 Department of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Krakow, Poland.
  • 10 Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 142 20, Prague, Czech Republic.
  • 11 University of Hradec Kralove, Department of Chemistry, Hradecka 1285, 500 01, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
  • 12 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic. Electronic address: ondrej.soukup@fnhk.cz.
  • 13 National Institute of Mental Health, Topolova 748, Klecany, 250 67, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic. Electronic address: jan.korabecny@fnhk.cz.
PMID: 35176563 DOI: 10.1016/j.ejmech.2022.114193
Abstract

Schizophrenia is a serious mental disorder without a fully understood pathomechanism, but which involves dysregulation of neurotransmitters and their receptors. The best option for the management of schizophrenia comprises so-called multi-target ligands, similar to the third generation of neuroleptics. Dopamine type 2 receptors (D2Rs) are the main target in the treatment of schizophrenia, in particular for mitigation of the positive symptoms. Due to the high expression of 5-hydroxytryptamine type 3 receptors (5-HT3Rs) in human brain areas responsible for emotional behavior, motivation, and cognitive function, 5-HT3Rs represent a potential target for modulating the cognitive and negative symptoms of schizophrenia. Here we present the design, synthesis, and both in vitro and in vivo biological evaluation of 1,4-disubstituted aromatic piperazines. Screening of in vitro properties revealed the two most promising drug candidates (21 and 24) which were found to be potent D2Rs and moderate 5-HT3R antagonists, and which were forwarded to in vivo studies in Wistar rats. Considering toxicity, administration of the maximal feasible dose of 21 (2 mg/kg) did not produce any side effects. By contrast, the higher solubility of 24 led to revelation of mild and temporary side effects at the dose of 20 mg/kg. Importantly, both 21 and 24 showed facile crossing of the blood-brain barrier, even exerting higher levels in the brain in comparison to plasma. In a behavioral study using the acute amphetamine model of psychosis, we showed that compound 24 ameliorated both positive and negative effects of amphetamine including hyperlocomotion, social impairments, and disruption of prepulse inhibition. The effect of the highest dose (10 mg/kg) was comparable to the effect of the reference dose of aripiprazole (1 mg/kg).

Keywords

1,4-Di-substituted aromatic piperazines; Antipsychotic; Aripiprazole; Cariprazine; Dopamine type 2 receptor; Drug development; Schizophrenia; Serotonin receptor type 3.

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