Počet záznamů: 1
Novel D-2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment
- 1.
SYSNO ASEP 0556370 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Novel D-2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment Tvůrce(i) Jůza, R. (CZ)
Vojtěchová, I. (CZ)
Štefková-Mazochová, K. (CZ)
Dehaen, W. (CZ)
Petrásek, T. (CZ)
Prchal, L. (CZ)
Kobrlová, T. (CZ)
Janoušek, J. (CZ)
Vlček, P. (CZ)
Mezeiová, E. (CZ)
Svozil, D. (CZ)
Zdarová Karasová, J. (CZ)
Pejchal, J. (CZ)
Stark, H. (DE)
Satala, G. (PL)
Bojarski, A. J. (PL)
Kubacka, M. (PL)
Mogilski, S. (PL)
Randáková, Alena (FGU-C) RID, ORCID
Musílek, K. (CZ)
Soukup, O. (CZ)
Korábečný, J. (CZ)Celkový počet autorů 22 Číslo článku 114193 Zdroj.dok. European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
Roč. 232, Mar 15 (2022)Poč.str. 20 s. Jazyk dok. eng - angličtina Země vyd. FR - Francie Klíč. slova aripiprazole ; cariprazine ; dopamine type 2 receptor ; drug development ; serotonin receptor type 3 ; schizophrenia ; 1,4-Di-substituted aromatic piperazines ; antipsychotic Obor OECD Pharmacology and pharmacy Způsob publikování Omezený přístup Institucionální podpora FGU-C - RVO:67985823 UT WOS 000766097300014 EID SCOPUS 85124454815 DOI https://doi.org/10.1016/j.ejmech.2022.114193 Anotace Schizophrenia is a serious mental disorder without a fully understood pathomechanism, but which in-volves 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 (D(2)Rs) 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 re-ceptors (5-HT(3)Rs) in human brain areas responsible for emotional behavior, motivation, and cognitive function, 5-HT(3)Rs 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 D(2)Rs and moderate 5-HT3R an-tagonists, and which were forwarded to in vivo studies in Wistar rats. Considering toxicity, adminis-tration 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). Pracoviště Fyziologický ústav Kontakt Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Rok sběru 2023 Elektronická adresa https://doi.org/10.1016/j.ejmech.2022.114193
Počet záznamů: 1