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Antiarrhythmic and α‐Adrenoceptor Antagonistic Properties of Novel Arylpiperazine Derivatives of Pyrrolidin‐2‐one
Author(s) -
Zaręba Paula,
Dudek Magdalena,
Lustyk Klaudia,
Siwek Agata,
Starowicz Gabriela,
Bednarski Marek,
Nowiński Leszek,
Zygmunt Małgorzata,
Sapa Jacek,
Malawska Barbara,
Kulig Katarzyna
Publication year - 2015
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201500180
Subject(s) - chemistry , adrenergic receptor , pharmacology , stereochemistry , receptor , biochemistry , medicine
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.