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

R. Juza, I. Vojtechova, K. Stefkova-Mazochova, W. Dehaen, T. Petrasek, L. Prchal, T. Kobrlova, J. Janousek, P. Vlcek, E. Mezeiova, D. Svozil, JZ. Karasova, J. Pejchal, H. Stark, G. Satala, AJ. Bojarski, M. Kubacka, S. Mogilski, A. Randakova, K....

. 2022 ; 232 (-) : 114193. [pub] 20220209

Language English Country France

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc22010758

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).

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$a Juza, Radomir $u National Institute of Mental Health, Topolova 748, Klecany, 250 67, Czech Republic; University of Hradec Kralove, Department of Chemistry, Hradecka 1285, 500 01, Hradec Kralove, Czech Republic
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$a Novel D2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment / $c R. Juza, I. Vojtechova, K. Stefkova-Mazochova, W. Dehaen, T. Petrasek, L. Prchal, T. Kobrlova, J. Janousek, P. Vlcek, E. Mezeiova, D. Svozil, JZ. Karasova, J. Pejchal, H. Stark, G. Satala, AJ. Bojarski, M. Kubacka, S. Mogilski, A. Randakova, K. Musilek, O. Soukup, J. Korabecny
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$a 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).
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$a Stefkova-Mazochova, Kristyna $u National Institute of Mental Health, Topolova 748, Klecany, 250 67, Czech Republic
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$a Dehaen, Wim $u Department of Informatics and Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology Prague, Technicka 5, 166 28, Prague, Czech Republic
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$a Petrasek, Tomas $u National Institute of Mental Health, Topolova 748, Klecany, 250 67, Czech Republic
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$a Karasova, Jana Zdarova $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic
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