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The Subtype Selectivity in Search of Potent Hypotensive Agents among 5,5-Dimethylhydantoin Derived α₁-Adrenoceptors Antagonists.

ABSTRACT: In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (1-15) 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 7-9. All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α₁-adrenergic receptors (α₁-AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α₁-adrenoceptor than urapidil in radioligand binding assay. Docking to two subtypes of adrenergic receptors, α_1A and α_1B, was conducted. Selected compounds were tested for their activity towards two α₁-AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds (1 and 5), which possess o-methoxyphenylpiperazine fragments, strong activity (IC₅₀ < 100 nM) was observed. Some representatives (3 and 5), which contain alkyl linker, proved selectivity towards α_1A-AR, while two compounds with 2-hydroxypropyl linker (11 and 13) to α_1B-AR. Finally, hypotensive activity was examined in rats. The most active compound (5) proved not only a lower effective dose than urapidil but also a stronger effect than prazosin.

SUBMITTER: Kaczor A

PROVIDER: S-EPMC10706087 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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The Subtype Selectivity in Search of Potent Hypotensive Agents among 5,5-Dimethylhydantoin Derived α1-Adrenoceptors Antagonists.

Kaczor Aneta A Knutelska Joanna J Kucwaj-Brysz Katarzyna K Zygmunt Małgorzata M Żesławska Ewa E Siwek Agata A Bednarski Marek M Podlewska Sabina S Jastrzębska-Więsek Magdalena M Nitek Wojciech W Sapa Jacek J Handzlik Jadwiga J

International journal of molecular sciences 20231122 23

In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (1-15) 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 7-9. All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α1-adrenergic receptors (α1-AR ...[more]

PMID: 38068933

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Dataset Information

The Subtype Selectivity in Search of Potent Hypotensive Agents among 5,5-Dimethylhydantoin Derived α₁-Adrenoceptors Antagonists.

Publications

The Subtype Selectivity in Search of Potent Hypotensive Agents among 5,5-Dimethylhydantoin Derived α<sub>1</sub>-Adrenoceptors Antagonists.

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