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

Structure‐Activity Relationship Studies of a Number of α1‐Adrenoceptor Antagonists and Antiarrhythmic Agents

“…In our pharmacological studies compounds 1-3, 21, 25, 28, 34-38, 44, 50 showed comparable profile at a dosages 5 mg/kg (i.v.). [29][30][31][32][33] Additionally, in a few last publications of Muramatsu et al [53,54] [29][30][31][32][33] The lowest affinity reported in the literature and still considered as reasonable is for BMY 7378 (pK i = 6.2) [53] and (pK i = 5.7). [54] According to this we believe that affinities of our compounds, although low are still within the range of typical a 1 -AR antagonist.…”

“…Antiarrhythmic activity was expressed as ÀlogED 50 (mM/kg) values in adrenaline induced arrhythmia in anaesthetized rats. [37] All pharmacological data obtained from references [29][30][31][32][33] are listed in Table 1. It was observed that the most active compounds are substituted in the ortho-position of the phenylpiperazinyl fragment of the molecule and it could play a crucial role in improving the a 1 -AR antagonist properties in terms of affinity and selectivity, together with antiarrhythmic action.…”

“…The analogues of 1-[3-(4-arylpiperazin-1-yl)propyl]pyrrolidin-2-one were chosen from our reports published between 2002 and 2009. [29][30][31][32][33] The source publications describe the synthesis of over 90 arylpiperazine derivatives and their pharmacological evaluation. About 30 compounds showed a lack of a 1 -ARs activity.…”

“…Biological activity data of the a 1 -ARs affinities, expressed as pK i values (Àlog K i , mM), using rat cerebral cortex tissue and [ 3 H]-prazosin as radioligand were presented. [29][30][31][32][33] Each K i value was obtained from three independent experiments. Antiarrhythmic activity was expressed as ÀlogED 50 (mM/kg) values in adrenaline induced arrhythmia in anaesthetized rats.…”

“…[26][27][28] We have previously reported that a series of 4-arylpiperazin-1-yl-propyl-pyrrolidin-2-one or 3-alkyl-3-phenylpyrrolidin-2-one derivatives possess affinity for a 1 -and a 2 -ARs and show marked hypertensive and AA activities. [29][30][31][32][33] Current drug discovery methods estimate biological response of potential medicinal agents by constructing independent and linear models. Although these models provide a link between specific biological targets and therapeutic effects, the properties of natural signals are too complex to expect that an independent set of descriptors would be capable of forecasting biological responses.…”