Premium
Synthesis, 3D‐QSAR, and Structural Modeling of Benzolactam Derivatives with Binding Affinity for the D 2 and D 3 Receptors
Author(s) -
López Laura,
Selent Jana,
Ortega Raquel,
Masaguer Christian F.,
Domínguez Eduardo,
Areias Filipe,
Brea José,
Loza María Isabel,
Sanz Ferran,
Pastor Manuel
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000101
Subject(s) - affinities , binding affinities , quantitative structure–activity relationship , receptor , stereochemistry , chemistry , hydrogen bond , ligand (biochemistry) , binding site , binding pocket , molecule , biochemistry , organic chemistry
A series of 37 benzolactam derivatives were synthesized, and their respective affinities for the dopamine D 2 and D 3 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 D 2 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 D 2 receptor which is absent in the D 3 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.