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Title: Psychotropic activity of long chain azinesulfonamide-arylpiperazine derivatives


Disertation presents findings of pharmacological in vitro and in vivo studies evaluating functional effects of newly synthesized two series of long-chain azinesulfonamide-arylpiperazine derivatives. The other aim of this study was the attempt to clarify mechanism of their potential psychotropic activity. Aripiprazole was used as a reference the 3rd generation antipsychotic drug.In radioligand studies in vitro, carried out for 12 compounds belonging to the series of quinoline- or isoquinoline-sulfonamide derivatives of monochlorophenylpiperazine and 14 quinoline- or isoquinoline-sulfonamide derivatives of 2,3-dichlorophenylpiperazine, monoaminergic receptor binding profile has been determined. Of the analogs tested, five compounds were selected from each series (respectively, PZ-395, PZ-397, PZ-493, PZ-510, PZ-511 and PZ-380, PZ-387, PZ-508, PZ-549, PZ-599), for which intrinsic activity has been evaluated in vitro and/or in vivo to specific receptors (presynaptic 5-HT1A receptor  body temperature in mice, postsynaptic 5-HT1A receptor  lower lip retraction test in rats, 5-HT2A receptor  head-twitch responses in mice, D2 receptor  climbing in mice, determining a level of cAMP in vitro in CHO cells expressing the human 5-HT1A or 5-HT7 receptor). Compounds with the most favorable functional profile was further investigated, the aim was to determine their psychotropic activity in ; vivo. In order to verify potential antipsychotic and cataleptogenic activity (PZ-395, PZ-511, PZ-508, PZ-549 and PZ-599)  the locomotor hyperactivity induced by D-amphetamine and/or MK-801 was performed and the bar test, respectively, in mice; antidepressant activity (PZ-395, PZ-397, PZ-493, PZ-510, PZ-511, PZ-380, PZ-387, PZ-508, PZ-549 and PZ-599)  the forced swim test in mice, anxiolytic activity (the four plates test in mice, the burying test in mice, the conflict drinking Vogel test in rats, the elevated plus maze test in rats). The specificity of each effect has been confirmed by appropriate control tests. ; It has been shown that the tested molecules are characterized by a significant affinity for the 5-HT1A, 5-HT2A, 5-HT7 and D2 receptors. Monochlorophenylpiperazine derivatives seem to be: 5-HT2A/D2 antagonists (PZ-397, PZ-493 and PZ-510), compound PZ-395 - an antagonist of 5-HT1A/5-HT2A/5-HT7/D2 receptors, and a derivative PZ-511  an antagonist of 5-HT2A/5-HT7/D2 ones. Among derivatives of 2,3-dichlorophenylpiperazine PZ-387, PZ-549 and PZ-599 have been found as partial receptor agonists of D2/5-HT2A and postsynaptic 5-HT1A antagonist, PZ-508  a partial agonist of D2 and 5-HT1A/5-HT2A antagonist and PZ-380  a partial agonist of D2/5-HT2A antagonist.In vivo experiments indicate that from the series of monochlorophenylpiperazine derivatives, a compound PZ-511 produ ; ces antipsychotic, antidepressant and anxiolytic activity. Among analogs of 2,3-dichlorophenylpiperazine, PZ-508 is a potential antipsychotic compound with an antidepressant component, and two analogs PZ-549 and PZ-599 evoke antidepressant and anxiolytic effects. The study has also been an attempt to determine the mechanism of action produced by selected, new derivatives. The obtained data show a positive interaction of the tested compounds with antidepressants which affect transmission by strengthening noradrenergic and/or serotoninergic one i.e. imipramine and S-citalopram and the anxiolytic drug  diazepam. The participation of 5-HT1A receptors in the antidepressant and anxiolytic activity of PZ-549 and PZ-599 has been excluded. ; The results of pharmacological experiments with two series of newly synthesized compounds belonging to a widely studied group of azinesulfonamide derivatives of long-chain arylpiperazines, confirm the desirability of searching for multireceptor profile compounds as potential psychotropic drugs, which can be used to treat mental illnesses. This study meets the contemporary trends in the search for new, more effective neuroleptics with no latency time, since currently available drugs are not effective or safe satisfactorily. The most active compounds, selected in these studies, will be used for further research to broaden the knowledge of their centr ; al activity profile. The data obtained from these studies will complete a gap in our knowledge of the chemical structure-affinity-pharmacological activity relationships in this group of derivatives as well.

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2 - studia doktoranckie

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Wydział Farmaceutyczny


Wesołowska, Anna

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Mar 20, 2023

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ZB-120921 Mar 20, 2023


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