title: Antiarrhythmic and α-Adrenoceptor Antagonistic Properties of Novel Arylpiperazine Derivatives of Pyrrolidin-2-one.
abstract: 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 α(1A)- and α(1B)-adrenoceptors and in vitro for antiarrhythmic activity in epinephrine-induced arrhythmia in rats. The highest affinity for the α1-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 α2-adrenoceptor (pK(i) = 6.52). Intrinsic activity studies of compound 9 showed that this compound is an antagonist of both α(1A)- (EC50 = 0.5 nM) and α(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 α1 -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.
authors.affiliation: Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Paula
authors.initials: P
authors.lastname: Zaręba
authors.affiliation: Department of Pharmacodynamics, Jagiellonian University, Collegium Medicum, Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Dudek
authors.affiliation: Department of Pharmacological Screening, Medical College, Jagiellonian University, Kraków, Poland.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Lustyk
authors.affiliation: Department of Pharmacobiology, Jagiellonian University, Collegium Medicum, Kraków, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: Department of Pharmacobiology, Jagiellonian University, Collegium Medicum, Kraków, Poland.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Starowicz
authors.affiliation: Department of Pharmacological Screening, Medical College, Jagiellonian University, Kraków, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Bednarski
authors.affiliation: Department of Pharmacodynamics, Jagiellonian University, Collegium Medicum, Kraków, Poland.
authors.forename: Leszek
authors.initials: L
authors.lastname: Nowiński
authors.affiliation: Department of Pharmacological Screening, Medical College, Jagiellonian University, Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Zygmunt
authors.affiliation: Department of Pharmacological Screening, Medical College, Jagiellonian University, Kraków, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Sapa
authors.affiliation: Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
authors.affiliation: Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kulig
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016466:CHO Cells; D003412:Cricetulus; D004195:Disease Models, Animal; D015195:Drug Design; D004837:Epinephrine; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C547713:ADRA1A protein, human; C547716:ADRA1B protein, human; D058668:Adrenergic alpha-1 Receptor Antagonists; D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D011760:Pyrrolidinones; D018340:Receptors, Adrenergic, alpha-1; D004837:Epinephrine
keywords: Antiarrthythmic; Arylpiperazine; Pyrrolidin-2-one