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Open Access Synthesis, α-adrenoceptors affinity and α1-adrenoceptor antagonistic properties of some 1,4-substituted piperazine derivatives

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A series of different 1,4-substituted piperazine derivatives (1–11) was synthesized. It comprised 1-(substituted-phenoxyalkyl)-4-(2-methoxyphenyl)piperazine derivatives (15); 1,4-bis(substituted-phenoxyethyl)piperazine derivatives (68) and 1-(substituted-phenoxy)-3-(substituted-phenoxyalkylpiperazin-1-yl)propan-2-ol derivatives (911). 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 Ki1) 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 Ki1) 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.

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Document Type: Research Article

Publication date: 2011-10-01

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