Synthesis and pharmacological evaluation of pyrrolidin-2-one derivatives as antiarrhythmic,antihypertensive and α-adrenolytic agents

A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment were synthesized and evaluated for their binding affinity for α1- and α2-adrenoceptors (ars) as well as their antiarrhythmic and antihypertensive activities. the highest affinity for the α1-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 α2-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. © 2010 by institute of pharmacology polish academy of sciences.