Antiarrhythmic and alpha-Adrenoceptor Antagonistic Properties of Novel Arylpiperazine Derivatives of Pyrrolidin-2-one

作者：Zareba Paula; Dudek Magdalena; Lustyk Klaudia; Siwek Agata; Starowicz Gabriela; Bednarski Marek; Nowinski Leszek; Zygmunt Malgorzata; Sapa Jacek; Malawska Barbara; Kulig Katarzyna^*

来源：Archiv der Pharmazie, 2015, 348(12): 861-867.

DOI：10.1002/ardp.201500180

• Antiarrthythmic
• Arylpiperazine
• Pyrrolidin-2-one

In an effort to develop a-adrenoceptor antagonists with antiarrhythmic activity, we designed a series of pyrrolidin-2-one derivatives. The alpha(1)- and alpha(2)-adrenorecepor affinities of the new pyrrolidin-2-one derivatives were determined using a radioligand binding assay. The most active compound was then tested in vitro for intrinsic activity toward alpha(1A)- and alpha(1B)-adrenoceptors and in vitro for antiarrhythmic activity in epinephrine-induced arrhythmia in rats. The highest affinity for the alpha(1)-adrenoceptor (pK(i) = 7.01) was displayed by 1-{4-[4-(2-methoxy-5-chlorophenyl)-piperazin-1-yl]-methyl}-pyrrolidin-2-one (9). 1-[4-(2-Fluorophenyl)-piperazin-1-yl]-methyl-pyrrolidin-2-one (7) showed the highest affinity toward the alpha(2)-adrenoceptor (pK(i) = 6.52). Intrinsic activity studies of compound 9 showed that this compound is an antagonist of both alpha(1A)-(EC50 = 0.5 nM) and alpha(1B)-(EC50 = 51.0 nM) adrenoceptors. Compound 9 displayed antiarrhythmic activity in rats (ED50 = 5.0 mg/kg (3.13-7.99)). New derivatives of pyrrolidin-2-one with alpha(1)-adrenoceptor affinity were identified. We propose that the antiarrhythmic activity of compound 9 is related to its antagonism of alpha(1A)- and alpha(1B)-adrenoceptors.

• 出版日期2015-12