The Subtype Selectivity in Search of Potent Hypotensive Agents among 5,5-Dimethylhydantoin Derived α<sub>1</sub>-Adrenoceptors Antagonists
In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (<b>1</b>–<b>15</b>) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microw...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-11-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/23/16609 |
| Summary: | In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (<b>1</b>–<b>15</b>) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microwaves, were carried out. Crystal structures were determined for compounds <b>7</b>–<b>9</b>. All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α<sub>1</sub>-adrenergic receptors (α<sub>1</sub>-AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α<sub>1</sub>-adrenoceptor than urapidil in radioligand binding assay. Docking to two subtypes of adrenergic receptors, α<sub>1A</sub> and α<sub>1B</sub>, was conducted. Selected compounds were tested for their activity towards two α<sub>1</sub>-AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds (<b>1</b> and <b>5</b>), which possess o-methoxyphenylpiperazine fragments, strong activity (IC<sub>50</sub> < 100 nM) was observed. Some representatives (<b>3</b> and <b>5</b>), which contain alkyl linker, proved selectivity towards α<sub>1A</sub>-AR, while two compounds with 2-hydroxypropyl linker (<b>11</b> and <b>13</b>) to α<sub>1B</sub>-AR. Finally, hypotensive activity was examined in rats. The most active compound (<b>5</b>) proved not only a lower effective dose than urapidil but also a stronger effect than prazosin. |
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| ISSN: | 1661-6596 1422-0067 |