Potentiometric quasi-array employing calixarene derivatives for the high-throughput similarity/diversity screening of beta-adrenergic and beta-blocking chiral drugs by HPLC.

Bazylak G; Nagels LJ; Geise HJ

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Potentiometric quasi-array employing calixarene derivatives for the high-throughput similarity/diversity screening of beta-adrenergic and beta-blocking chiral drugs by HPLC.

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Performance of potentiometric quasi-array detection system consisted with the seven poly (vinyl chloride) (PVC) based liquid membrane electrodes in the cation-exchange HPLC using acetonitrile--40 mM phosphoric acid (15 : 85, v/v, pH* 2.35) for assessing of molecular similarity/diversity in a mini-library of beta-adrenergic and beta-blocking chiral drugs was presented. Macrocyclic compounds differing in stability of their conformers as well as in a size, steric hindrance and polarity of its internal cavities, comprising a series of five calix6arene derivatives completed with one modified calix4resorcinarene, were used as neutral ionophores to compose mentioned set of PVC-based electrodes. The output potentiometric responses were registered in the linear supernerstian range of calibration graph of each electrode, i.e. for a constant injected concentration 2.0 x 10(-4) M of investigated drugs, which is related to the amount frequently used at in vitro studies on pharmacological effects of these drugs.The impact of symmetry oriented supramolecular interactions on the responses of developed electrodes were characterised with proposed series of the highly significant quantitative structure-potentiometric response relationships (QSPRRs) combining both three-dimensional (3D) molecular descriptors of analysed drugs as well as lipophilicity and volume polarizability of calixarene-type ionophores. The principal components analysis (PCA) and unweighted hierarchical clustering analysis (HCA) were used as the pattern recognition techniques into collected potentiometric database for extraction of the useful information on the molecular and pharmacological similarity/diversity of analysed drugs, thus a high-throughput and consistent identification of therapeutically relevant agonists of beta2- and beta3-adrenoceptors and antagonists of beta1-adrenoceptor was especially achieved. This evidence supports also a hypothesis formulated by results of homology modelling on the subtle significance of an unrecognised supramolecular insertion processes of the chiral drug molecule into the flexible hydrophobic pocket(s) formed by seven helical transmembrane moving domains of beta-adrenoceptors on their final activation, sequestration, down-regulation or blockade.

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《Combinatorial chemistry & high throughput screening》 |2004年第4期|345-359|共15页
作者
Bazylak G; Nagels LJ; Geise HJ;
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作者单位

Department of Food Sciences & Drug Chemistry, Faculty of Pharmacy, Ludwik Rydygier Medical University, Jagiellonska 13, PL-85-067 Bydgoszcz, Poland. gbazylak@amb.bydgoszcz.pl;

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正文语种英语
中图分类化学;
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Adrenergic beta-Antagonists; Drug Evaluation; Preclinical; Polycyclic Hydrocarbons; 肾上腺素能β受体拮抗剂; 多环碳氢化合物; 受体; 肾上腺素能β;

Potentiometric quasi-array employing calixarene derivatives for the high-throughput similarity/diversity screening of beta-adrenergic and beta-blocking chiral drugs by HPLC.

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