The Structural Determinants for α<sub>1</sub>-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives
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 diso...
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2021
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oai:doaj.org-article:c378d5c166f349a6af1c3d5be2fa4bf72021-11-25T18:29:16ZThe Structural Determinants for α<sub>1</sub>-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives10.3390/molecules262270251420-3049https://doaj.org/article/c378d5c166f349a6af1c3d5be2fa4bf72021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/22/7025https://doaj.org/toc/1420-3049Several 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 <b>12</b> with multifunctional adrenergic-serotonin activity, which is a promising candidate to be an effective anxiolytic agent; (b) compound <b>14</b> with high α<sub>1A</sub>/α<sub>1D</sub> affinity and selectivity towards α<sub>1B</sub>, which is recommended due to the elimination of probable cardiotoxic effect<b>.</b> 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.Katarzyna Kucwaj-BryszAnna DelaSabina PodlewskaMarek BednarskiAgata SiwekGrzegorz SatałaKinga CzarnotaJadwiga HandzlikKatarzyna Kieć-KononowiczMDPI AGarticleadrenergic receptorsserotonin receptorsG protein-coupled receptorsselectivitydockingmolecular dynamicsOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 7025, p 7025 (2021) |
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DOAJ |
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EN |
| topic |
adrenergic receptors serotonin receptors G protein-coupled receptors selectivity docking molecular dynamics Organic chemistry QD241-441 |
| spellingShingle |
adrenergic receptors serotonin receptors G protein-coupled receptors selectivity docking molecular dynamics Organic chemistry QD241-441 Katarzyna Kucwaj-Brysz Anna Dela Sabina Podlewska Marek Bednarski Agata Siwek Grzegorz Satała Kinga Czarnota Jadwiga Handzlik Katarzyna Kieć-Kononowicz The Structural Determinants for α<sub>1</sub>-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives |
| description |
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 <b>12</b> with multifunctional adrenergic-serotonin activity, which is a promising candidate to be an effective anxiolytic agent; (b) compound <b>14</b> with high α<sub>1A</sub>/α<sub>1D</sub> affinity and selectivity towards α<sub>1B</sub>, which is recommended due to the elimination of probable cardiotoxic effect<b>.</b> 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. |
| format |
article |
| author |
Katarzyna Kucwaj-Brysz Anna Dela Sabina Podlewska Marek Bednarski Agata Siwek Grzegorz Satała Kinga Czarnota Jadwiga Handzlik Katarzyna Kieć-Kononowicz |
| author_facet |
Katarzyna Kucwaj-Brysz Anna Dela Sabina Podlewska Marek Bednarski Agata Siwek Grzegorz Satała Kinga Czarnota Jadwiga Handzlik Katarzyna Kieć-Kononowicz |
| author_sort |
Katarzyna Kucwaj-Brysz |
| title |
The Structural Determinants for α<sub>1</sub>-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives |
| title_short |
The Structural Determinants for α<sub>1</sub>-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives |
| title_full |
The Structural Determinants for α<sub>1</sub>-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives |
| title_fullStr |
The Structural Determinants for α<sub>1</sub>-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives |
| title_full_unstemmed |
The Structural Determinants for α<sub>1</sub>-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives |
| title_sort |
structural determinants for α<sub>1</sub>-adrenergic/serotonin receptors activity among phenylpiperazine-hydantoin derivatives |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/c378d5c166f349a6af1c3d5be2fa4bf7 |
| work_keys_str_mv |
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| _version_ |
1718411103073992704 |