Synthesis and pharmacological evaluation of new 1-[3-(4-phenylpiperazin-1-yl)-propyl]- and 1-[3-(4-phenylpiperidine)-propyl]- 3-aryl-3-alkyl-pyrrolidin-2-one derivatives with antiarrhythmic and antihypertensive activity.
Acta poloniae pharmaceutica 2009 Nov 1; 66(6):649-62
Kulig K, Sapa J, Nowaczyk A, Filipek B, Malawska B
Department of Physicochemical Drug Analysis, Pharmaceutical Faculty, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Kraków, Poland. mfkkulig@cyf-kr.edu.pl
A series of novel phenylpiperazine and phenylpiperidine derivatives bearing a 3,3-disubstituted pyrrolidin-2-one fragment were synthesized and evaluated for their binding affinity for alpha1-adrenoceptors (ARs) and for their antiarrhythmic and antihypertensive activities. The highest affinity for alpha1-ARs was displayed by 1-[2-hydroxy-3-(4-phenylpiperazin-l-yl)-propyl]-3-phenyl-3-n-propyl-pyrrolidin-2-one (10 a), which binds with pK(i) = 6.43. Among the compounds tested, 1-(2-hydroxy-3-(4-phenylpiperidin-1-yl)-propylpyrrolidin-2-one (5) was the most active in the prophylactic antiarrhythmic activity in adrenaline induced arrhythmia in anesthetized rats. Its ED50 value was 4.9 mg/kg intravenously (i.v.). Some of the compounds tested significantly decreased the systolic and diastolic pressure in normotensive anesthetized rats at a dose of 5.0 mg/kg i.v. and their hypotensive effects lasted for longer than an hour.
Keywords: antiarrhythmic antihypertensive