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

Abstract

Arylpiperazines represent one of the most studied classes of α1 -adrenoceptor (α1 -AR) antagonists. Currently, α1 -AR antagonists are useful in the treatment of benign prostatic hyperplasia, lower urinary tract symptoms or cardiac arrhythmia. The activity of various derivatives of 1-[3-(4-arylpiperazin-1-yl)propyl]pyrrolidin-2-one as α1 -adrenergic receptor antagonists and antiarrhythmic (AA) agents was described using the qualitative inverse Structure Activity Relationship (SAR) model. The three-dimensional structures of the pyrrolidin-2-one derivatives in the basic form were obtained using AM1 semi-empirical quantum chemical calculations. All the molecules were geometry-optimized until the root-mean-square (RMS) gradient value was smaller than 10(-6) a.u. Single-point energy (SPE) calculations were performed at the DFT/B3LYP level of theory using the 6-31G** basis set. The main focus of this inverse SAR study is to find which features cause enhancing of antiarrhythmic properties between subtly different types of activity (α1 -adrenoreceptor antagonists and antiarrhythmic activities). Our SAR study involves the charge distribution in the plane of the pharmacophore model for α1 -AR. Suitable maps of the electrostatic potential were plotted based on the electronic and nuclear charge distribution obtained from the energy calculations. The results of this modelling study indicate that if the terminal arylpiperazine moiety is surrounded by regions of negative electrostatic potential, then the antiarrhythmic activity is blocked.

QSAR studies on a number of pyrrolidin-2-one antiarrhythmic arylpiperazinyls

“…Because the sign of the regression coefficient is positive, a decrease of this predictor will result in a decrease in AA stimulation. Our earlier qualitative investigations (SAR) led us to similar conclusions (Kulig et al ., 2007 ; Nowaczyk et al , 2009 , 2010 ). The remaining parameter of the model (Hy) is the hydrophilic factor.…”

Antiarrhythmic and antioxidant activity of novel pyrrolidin-2-one derivatives with adrenolytic properties

“…However if this is truth the α 1 -AR affinity and/or antiarrhythmic activity of investigated set should differ insignificantly, which does not fit to our pharmacological data. The (Q)SAR study was already published (Nowaczyk et al 2009 , 2010 ). In this work, we describe application of computational of biological activity spectra according to which the compound’s biological activity is considered as an intrinsic property of the structure.…”