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, α1A and α1B, 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 α1A-AR, while two compounds with 2-hydroxypropyl linker (11 and 13) to α1B-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.