1350302-29-2Relevant academic research and scientific papers
Synthesis, α-adrenoceptors affinity and α1- adrenoceptor antagonistic properties of some 1,4-substituted piperazine derivatives
Marona,Kubacka,Filipek,Siwek,Dybala,Szneler,Pociecha,Gunia,Waszkielewicz, Anna M.
scheme or table, p. 733 - 739 (2012/03/10)
A series of different 1,4-substituted piperazine derivatives (1-11) was synthesized. It comprised 1- (substituted-phenoxyalkyl)-4-(2-methoxyphenyl) piperazine derivatives (1-5); 1,4-bis(substituted-phenoxyethyl)piperazine derivatives (6-8) and 1-(substituted-phenoxy)-3-(substituted- phenoxyalkylpiperazin-1-yl)propan-2-ol derivatives (9-11). All compounds were evaluated for affinity toward α1- and α2- receptors by radioligand binding assays on rat cerebral cortex using [ 3H]prazosin and [3H]clonidine as specific radioligand, respectively. Furthermore α1-antagonistic properties were checked for most promising compounds (1-5 and 10) by means of inhibition of phenylephrine induced contraction in isolated rat aorta. Antagonistic potency stayed in agreement with radioligand binding results. The most active compounds (1-5) displaced [3H]prazosin from cortical binding sites in low nanomolar range (Ki = 2.1-13.1 nM). Compound 10 showed slightly lower affinity for α1-adrenoceptor (Ki = 781 nM). Compounds 2-5 displayed the strongest antagonistic activity with pA2 values ranging from 8.441 to 8.807. Compound 1 gave a pA2 value of 7.868, while compound 10 showed the weakest antagonistic potency, giving a pA2 value of 6.374. 1-[3-(2-Chloro-6-methylphenoxy)propyl]-4-(2- methoxyphenyl)piperazine hydrochloride (5) showed the best α1- affinity properties with a Ki(α1) value of 2.1 nM and it was 61.05 fold more selective toward α1 than α2-receptors. The best properties showed 1-[3-(2,6- dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (4) with a Ki(α1) value of 2.4 nM, a 142.13 fold better selectivity to α1- over α2-adrenoceptors and the best antagonistic potency (pA2 = 8.807). It is worth to emphasized that all most promising compounds possessed an 1-(o-methoxyphenyl) piperazine moiety which probably plays an important role in the affinity to α-adrenoceptors.
