title: Alpha(1) adrenoceptor subtype selectivity. 3D-QSAR models for a new class of alpha(1) adrenoceptor antagonists derived from the novel antipsychotic sertindole.
abstract: Receptor-binding affinities for the alpha(1) adrenoceptor subtypes alpha(1a), alpha(1b) and alpha(1d) for a series of 39 alpha(1) adrenoceptor antagonists derived from the antipsychotic sertindole are reported. The SAR of the compounds with respect to affinity for the alpha(1a), alpha(1b) and alpha(1d) adrenoceptor subtypes as well as affinity obtained by an alpha(1) assay (rat brain membranes) were investigated using a 3D-QSAR approach based on the GRID/GOLPE methodology. Good statistics (r(2)=0.91-0.96; q(2)=0.65-0.73) were obtained with the combination of the water (OH2) and methyl (C3) probes. The combination of steric repulsion and electrostatic attractions explain the affinities of the included molecules. The adrenergic alpha(1a) receptor seems to be more tolerant to large substituents in the area between the indole 5- and 6-positions compared to the adrenergic alpha(1b) and alpha(1d) receptor subtypes. There seems to be minor differences in the position of areas in the alpha(1b) receptor compared to alpha(1a) and alpha(1d) receptors where electrostatic interaction between the molecules and the receptor (OH2 probe) contribute to increased affinity. These observations may be used in the design of new subtype selective compounds. In addition, the model based on biological data from an alpha(1) assay (rat brain membranes) resembles the model for the alpha(1b) adrenoceptor subtype.
authors.affiliation: Medicinal Chemistry Research, H Lundbeck A/S, 9 Ottiliavej, 2500 Valby, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
authors.forename: Kim
authors.initials: K
authors.lastname: Andersen
authors.forename: Karina Krøjer
authors.initials: KK
authors.lastname: Søby
authors.forename: Tommy
authors.initials: T
authors.lastname: Liljefors
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D015195:Drug Design; D007093:Imidazoles / Q000737:chemistry*; D007211:Indoles / Q000737:chemistry*; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D007093:Imidazoles; D007211:Indoles; C066304:sertindole