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Hybrid approach for the design of highly affine and selective dopamine D(3) receptor ligands using privileged scaffolds of biogenic amine GPCR ligands.

Sasse BC, Mach UR, Leppaenen J, Calmels T, Stark H

Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.

A series of compounds containing privileged scaffolds of the known histamine H(1) receptor antagonists cetirizine, mianserin, ketotifen, loratadine, and bamipine were synthesized for further optimization as ligands for the related biogenic amine binding dopamine D(3) receptor. A pharmacological screening was carried out at dopamine D(2) and D(3) receptors. In the preliminary testing various ligands have shown moderate to high affinities for dopamine D(3)receptors, for example, N-(4-{4-[benzyl(phenyl)amino]piperidin-1-yl}butylnaphthalen-2-carboxamide (19a) (hD(3)K(i)=0.3 nM; hD(2)K(i)=703 nM), leading to a selectivity ratio of 2343.

Published 15 October 2007 in Bioorg Med Chem, 15(23): 7258-73.
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