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

In an effort to develop α‐adrenoceptor antagonists with antiarrhythmic activity, we designed a series of pyrrolidin‐2‐one derivatives. The α1‐ and α2‐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 α1A‐ and α1B‐adrenoceptors and in vitro for antiarrhythmic activity in epinephrine‐induced arrhythmia in rats. The highest affinity for the α1‐adrenoceptor (pKi = 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 α2‐adrenoceptor (pKi = 6.52). Intrinsic activity studies of compound 9 showed that this compound is an antagonist of both α1A‐ (EC50 = 0.5 nM) and α1B‐ (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 α1‐adrenoceptor affinity were identified. We propose that the antiarrhythmic activity of compound 9 is related to its antagonism of α1A‐ and α1B‐adrenoceptors. A series of new pyrrolidin‐2‐one derivatives (2–12) were synthetized and assessed for their α‐adrenoceptor affinity. The most promising compound (9) was further tested for its antiarrhythmic activity, which turned out to be related to its antagonism at the α1A‐ and α1B‐adrenoceptors.