Novel D-2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment

0556370 - FGÚ 2023 RIV FR eng J - Článek v odborném periodiku
Jůza, R. - Vojtěchová, I. - Štefková-Mazochová, K. - Dehaen, W. - Petrásek, T. - Prchal, L. - Kobrlová, T. - Janoušek, J. - Vlček, P. - Mezeiová, E. - Svozil, D. - Zdarová Karasová, J. - Pejchal, J. - Stark, H. - Satala, G. - Bojarski, A. J. - Kubacka, M. - Mogilski, S. - Randáková, Alena - Musílek, K. - Soukup, O. - Korábečný, J.
Novel D-2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment.
European Journal of Medicinal Chemistry. Roč. 232, Mar 15 (2022), č. článku 114193. ISSN 0223-5234. E-ISSN 1768-3254
Institucionální podpora: RVO:67985823
Klíčová 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
Impakt faktor: 6.7, rok: 2022
Způsob publikování: Omezený přístup
https://doi.org/10.1016/j.ejmech.2022.114193

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).
Trvalý link: http://hdl.handle.net/11104/0330742