title: Synthesis and pharmacological evaluation of pyrrolidin-2-one derivatives as antiarrhythmic, antihypertensive and alpha-adrenolytic agents.
abstract: A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment were synthesized and evaluated for their binding affinity for alpha1- and alpha2-adrenoceptors (ARs) as well as their antiarrhythmic and antihypertensive activities. The highest affinity for the alpha1-AR was displayed by 1-{3-[4-(2-chloro-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 7, which binds with a pKi = 7.13. The highest affinity for the alpha2-AR was shown by 1-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 18, which binds with a pKi = 7.29. Among the compounds tested, 1-{3-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 13 had the highest prophylactic antiarrhythmic activity in epinephrine-induced arrhythmia in anesthetized rats. Its ED50 value was 1.0 mg/kg intravenously (iv). The compounds with a hydroxy group in the 4-position of the phenyl ring or two substituents such as fluorine atoms in the 2 and 4 positions of the phenyl ring significantly decreased systolic and diastolic pressure in normotensive anesthetized rats at a dose of 2.5 mg/ kg iv, and their hypotensive effects lasted for longer than an hour.
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland. mfkkulig@cyf-kr.edu.pl
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kulig
authors.forename: Cindy
authors.initials: C
authors.lastname: Spieces
authors.forename: Jacek
authors.initials: J
authors.lastname: Sapa
authors.forename: Christa
authors.initials: C
authors.lastname: Caspers
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000818:Animals; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000517:prevention & control; D001794:Blood Pressure / Q000187:drug effects; D002855:Chromatography, Thin Layer; D004837:Epinephrine; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D007202:Indicators and Reagents; D011760:Pyrrolidinones; D004837:Epinephrine