title: Synthesis and development of new 2-substituted 1-[3-(4-arylpiperazin-1-yl)propyl]-pyrrolidin-2-one derivatives with antiarrhythmic, hypotensive, and alpha-adrenolytic activity.
abstract: A series of new 1-[3-(4-arylpiperazinyl-1-yl)-2-(N-alkylcarbamoyloxy)propyl]-pyrrolidin-2-one derivatives (4a-12a) were synthesised and tested for their electrocardiographic, antiarrhythmic and antihypertensive activity, as well as for the alpha1- and alpha2-adrenoceptor binding affinities. Of the newly synthesised derivatives, 1-{2-(N-2-methylethylcarbamoiloxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl)]propyl}pyrrolidin-2-one dihydrochloride (10a) was the most active in prophylactic antiarrhythmic tests, its ED50 value equalling 2.7 mg kg(-1), and the therapeutic index being 75.2; moreover, compound 10a was also found to possess hypotensive activity. A preliminary molecular modelling study suggested that the selected alpha1-AR antagonist distances and angles between pharmacophoric features, estimated for the tested compounds, were in good agreement with the parameters evaluated for ligands.
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University, Medical College, 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: Annika
authors.initials: A
authors.lastname: Gippert
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
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000627:therapeutic use / Q000633:toxicity; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000627:therapeutic use / Q000633:toxicity; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000627:therapeutic use / Q000633:toxicity; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D023382:Toxicity Tests, Acute
chemical_list: D000316:Adrenergic alpha-Agonists; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D011759:Pyrrolidines; D011942:Receptors, Adrenergic, alpha