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Synthesis, 3D-QSAR, and structural modeling of benzolactam derivatives with binding affinity for the D<inf>2</inf>and D<inf>3</inf> receptors

Abstract:

A series of 37 benzolactam derivatives were synthesized, and their respective affinities for the dopamine D2 and D3 receptors evaluated. The relationships between structures and binding affinities were investigated using both ligand-based (3D-QSAR) and receptor-based methods. The results revealed the importance of diverse structural features in explaining the differences in the observed affinities, such as the location of the benzolactam carbonyl oxygen, or the overall length of the compounds. The optimal values for such ligand properties are slightly different for the D2 and D 3 receptors, even though the binding sites present a very high degree of homology. We explain these differences by the presence of a hydrogen bond network in the D2 receptor which is absent in the D3 receptor and limits the dimensions of the binding pocket, causing residues in helix 7 to become less accessible. The implications of these results for the design of more potent and selective benzolactam derivatives are presented and discussed. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.