Design, synthesis and pharmacological evaluation of new 1-[3-(4-arylpiperazin-1-yl)-2-hydroxy-propyl]-3,3-diphenylpyrrolidin-2-one derivatives with antiarrhythmic, antihypertensive, and α-adrenolytic activity

A series of novel arylpiperazines bearing a 3,3-diphenylpyrrolidin-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-ethoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3,3-diphenylpyrrolidin-2-one (7), which binds with a pKi = 7.28. The highest affinity for the α2-AR was shown by 1-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3,3-diphenylpyrrolidin-2-one (5), which binds with a pKi = 6.68. Compound 7 was additionally evaluated in in vitro functional tests for its affinity for α1B- and α1D-AR, which gave pA2 α1B = 6.55 and pA2 α1D = 7.26. Among the compounds tested, compound 7 also had the highest prophylactic antiarrhythmic activity in adrenaline-induced arrhythmia in anaesthetized rats. Its ED50 value was 1.1 mg/kg (i.v.). The compounds significantly decreased systolic and diastolic pressure in normotensive anaesthetized rats at doses of 2.5–5.0 mg/kg (i.v.) and their hypotensive effects lasted for longer than 1 h. It was found that the introduction of two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave compounds with affinity for both α1- and α2-AR. The substitution of the 2nd position in the phenyl piperazinyl fragment of the molecule was crucial for activity. To determine detailed information concerning the structure–activity relationship, a preliminary molecular modeling study was undertaken.

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