title: Synthesis, 3D-QSAR, and structural modeling of benzolactam derivatives with binding affinity for the D(2) and D(3) receptors.
abstract: 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.
authors.affiliation: GRIB, IMIM, DCEXS, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: López
authors.forename: Jana
authors.initials: J
authors.lastname: Selent
authors.forename: Raquel
authors.initials: R
authors.lastname: Ortega
authors.forename: Christian F
authors.initials: CF
authors.lastname: Masaguer
authors.forename: Eduardo
authors.initials: E
authors.lastname: Domínguez
authors.forename: Filipe
authors.initials: F
authors.lastname: Areias
authors.forename: José
authors.initials: J
authors.lastname: Brea
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Loza
authors.forename: Ferran
authors.initials: F
authors.lastname: Sanz
authors.forename: Manuel
authors.initials: M
authors.lastname: Pastor
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D007769:Lactams / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D017448:Receptors, Dopamine D2 / Q000737:chemistry* / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D007769:Lactams; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3