Conformational analyses on histamine H2-receptor antagonists |
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Authors: | Höltje Hans-Dieter Anita Batzenschlager |
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Affiliation: | (1) Institute of Pharmacy, Free University of Berlin, Königin-Luise-Strasse 2+4, W-1000 Berlin 33, Germany |
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Abstract: | Summary In a series of compounds with H2-antihistaminic activity, a conformational analysis was performed based on force field calculations. The drugs studied were cimetidine, ranitidine, famotidine, roxatidine and the conformationally more restricted ICI127032. For the compounds containing a flexible chain, the local minima conformations and the global minimum conformation were calculated. These conformations were used for a systematic structural comparison with all energetically allowed conformations of the ICI derivative, with regard to the best fit of the common structural features. In this way a pharmacophore could be developed consisting of four parts: (1) a polar planar group, uncharged at physiological pH; (2) a hydrophobic part formed by aromatic systems or flexible chains; (3) an—under physiological conditions—protonated nitrogen atom; and (4) a substructure, which contains a hydrogen bond donor site and a hydrogen bond acceptor site in a specific spatial arrangement. |
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Keywords: | H2-receptor antagonists Pharmacophore Conformational analysis |
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