Synthesis, computational and pharmacological evaluation of novel N-{4-[2-(4-aryl-piperazin-1-yl)ethyl]phenyl}-arylamides Scientific paper
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Abstract
Serotonin, or 5-hydroxytryptamine (5-HT), is a biogenic amine most noted as a neurotransmitter, an activator of the utmost subtype family of G-pro-tein-coupled receptors (GPCR). Drugs targeting 5-HT1A and other 5-HT receptors treat central nervous system diseases such as schizophrenia and depression. Recent advances in serotonin receptor structure research gave us several crystal 5-HT1A receptor structures, most notably 5-HT1A bound to the antipsychotic drug aripiprazole (Abilify®). This discovery prompted us to evaluate a series of newly synthesized ligands for serotonergic activity since those arylpiperazine derivatives share minimal general structure with aripiprazole. The results of molecular docking analysis of unsubstituted starting substances encouraged us to propound further modifications of the tail and head parts of the parent molecules to maximize receptor binding affinity. Intrigued by the results of molecular analysis, all foreseen derivatives were synthesized. The pharmacological activity of all nine (5a and 6a are synthesized previously) compounds was assessed by the in vitro tests and in silico pharmacokinetics predictions for the most promising candidates. All tested ligands have improved affinity compering to parent compounds (10a and 11a), 8b and 9b expressed the best pharmacological profile with an improved binding affinity toward serotonin 5-HT1A receptors (Ki 12.1 and 4.8 nM, respectively).
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This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution license 4.0 that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
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Ministarstvo Prosvete, Nauke i Tehnološkog Razvoja
Grant numbers 451-03-47/2023-01/200168 -
Ministarstvo Prosvete, Nauke i Tehnološkog Razvoja
Grant numbers 451-03-47/2023-01/200026
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