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.
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.
Kulig
Katarzyna
K
Department of Physicochemical Drug Analysis, Pharmaceutical Faculty, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Kraków, Poland. mfkkulig@cyf-kr.edu.pl
Sapa
Jacek
J
Nowaczyk
Alicja
A
Filipek
Barbara
B
Malawska
Barbara
B
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D011760:Pyrrolidinones