title: 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.
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 9 Sklodowskiej-Curie Str., 85-094 Bydgoszcz, Poland phone: (+4852) 585 39 04 fax: (+4852) 585 39 20. alicja@cm.umk.pl.
authors.forename: Alicja
authors.initials: A
authors.lastname: Nowaczyk
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 9 Sklodowskiej-Curie Str., 85-094 Bydgoszcz, Poland phone: (+4852) 585 39 04 fax: (+4852) 585 39 20.
authors.forename: Rafał
authors.initials: R
authors.lastname: Przybylski
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Medical College Jagiellonian University, 9 Medyczna Str., 30-688 Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kulig
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Medical College Jagiellonian University, 9 Medyczna Str., 30-688 Kraków, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
keywords: 1-[3-(4-Arylpiperazin-1-yl)propyl]pyrrolidin-2-one derivatives; Antiarrhythmic activity; Drug design; Structure-activity relationships; α1-Adrenoceptor blocking activity