The Structural Determinants for α1-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives
| Autor: | Grzegorz Satała, Agata Siwek, Anna Dela, Katarzyna Kucwaj-Brysz, Kinga Czarnota, Marek Bednarski, Jadwiga Handzlik, Sabina Podlewska, Katarzyna Kieć-Kononowicz |
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| Rok vydání: | 2021 |
| Předmět: |
Adrenergic receptor
Intrinsic activity medicine.drug_class Pharmaceutical Science Phenylpiperazine Pharmacology Serotonergic Anxiolytic Analytical Chemistry chemistry.chemical_compound QD241-441 G protein-coupled receptors serotonin receptors Drug Discovery medicine Physical and Theoretical Chemistry 5-HT receptor Chemistry Organic Chemistry selectivity molecular dynamics Chemistry (miscellaneous) Docking (molecular) docking Molecular Medicine Serotonin adrenergic receptors |
| Zdroj: | Molecules Volume 26 Issue 22 Molecules, Vol 26, Iss 7025, p 7025 (2021) |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules26227025 |
| Popis: | Several studies confirmed the reciprocal interactions between adrenergic and serotoninergic systems and the influence of these phenomena on the pathogenesis of anxiety. Hence, searching for chemical agents with a multifunctional pharmacodynamic profile may bring highly effective therapy for CNS disorders. This study presents a deep structural insight into the hydantoin-arylpiperazine group and their serotonin/α-adrenergic activity. The newly synthesized compounds were tested in the radioligand binding assay and the intrinsic activity was evaluated for the selected derivatives. The computer-aided SAR analysis enabled us to answer questions about the influence of particular structural fragments on selective vs. multifunctional activity. As a result of the performed investigations, there were two leading structures: (a) compound 12 with multifunctional adrenergic-serotonin activity, which is a promising candidate to be an effective anxiolytic agent (b) compound 14 with high α1A/α1D affinity and selectivity towards α1B, which is recommended due to the elimination of probable cardiotoxic effect. The structural conclusions of this work provide significant support for future lead optimization in order to achieve the desired pharmacodynamic profile in searching for new CNS-modulating agents. |
| Databáze: | OpenAIRE |
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