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 α 1 ‐ and α 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 α 1A ‐ and α 1B ‐adrenoceptors and in vitro for antiarrhythmic activity in epinephrine‐induced arrhythmia in rats. The highest affinity for the α 1 ‐adrenoceptor (p K 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 α 2 ‐adrenoceptor (p K i  = 6.52). Intrinsic activity studies of compound 9 showed that this compound is an antagonist of both α 1A ‐ (EC 50  = 0.5 nM) and α 1B ‐ (EC 50  = 51.0 nM) adrenoceptors. Compound 9 displayed antiarrhythmic activity in rats (ED 50  = 5.0 mg/kg (3.13–7.99)). New derivatives of pyrrolidin‐2‐one with α 1 ‐adrenoceptor affinity were identified. We propose that the antiarrhythmic activity of compound 9 is related to its antagonism of α 1A ‐ and α 1B ‐adrenoceptors.