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

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 α 1 -adrenergic receptors (α 1 -AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α 1 -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 α 1 -AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds ( 1 and 5 ), which possess o-methoxyphenylpiperazine fragments, strong activity (IC 50 < 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.