title: Synthesis, antiarrhythmic, and antihypertensive effects of novel 1-substituted pyrrolidin-2-one and pyrrolidine derivatives with adrenolytic activity.
abstract: A series of 1-substituted pyrrolidin-2-one and pyrrolidine derivatives were synthesised and tested for electrocardiographic, antiarrhythmic, and antihypertensive activity as well as for alpha(1)- and alpha(2)-adrenoceptors binding affinities. Among the newly synthesised derivatives several compounds with 3-(4-arylpiperazin-1-yl)propyl moiety displayed strong antiarrhythmic (7a-12a) and antihypertensive (7a-11a) activities. Compound 11a, 1-[2-acetoxy-3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one, was the most potent in this series. The pharmacological results and binding studies suggest that their antiarrhythmic and hypotensive effects may be related to their alpha-adrenolytic properties, and that those properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or chloro- substituent in the ortho position in the phenyl ring.
authors.affiliation: Department of Pharmaceutical Chemistry, Collegium Medicum of Jagiellonian University, 9 Medyczna St., 30-688, Kraków, Poland. mfmalaws@cyf-kr.edu.pl
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kulig
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.forename: Jacek
authors.initials: J
authors.lastname: Sapa
authors.forename: Dorota
authors.initials: D
authors.lastname: Maciag
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Zygmunt
authors.forename: Lucyna
authors.initials: L
authors.lastname: Antkiewicz-Michaluk
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy; D001794:Blood Pressure / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D011485:Protein Binding; D011759:Pyrrolidines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D011760:Pyrrolidinones / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000317:Adrenergic alpha-Antagonists; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D011759:Pyrrolidines; D011760:Pyrrolidinones; D011942:Receptors, Adrenergic, alpha