title: New ligands with affinity for the alpha4beta2 subtype of nicotinic acetylcholine receptors. Synthesis, receptor binding, and 3D-QSAR modeling.
abstract: A new series of piperazines, diazepanes, diazocanes, diazabicyclononanes, and diazabicyclodecanes with affinity for the alpha4beta2 subtype of nicotinic acetylcholine receptors were synthesized on the basis of results from a previous computational study. A predictive 3D-QSAR model was developed using the GRID/GOLPE approach (R2 = 0.94, Q2 = 0.83, SDEP = 0.34). The SAR was interpreted in terms of contour maps of the PLS coefficients and in terms of a homology model of the alpha4beta2 subtype of the nicotinic acetylcholine receptors. The results reveal that hydrogen bonding from both hydrogens on the protonated amine and from the pyridine nitrogen to a water molecule as well as van der Waals interactions between the substituent bearing the protonated amine and the receptor is of importance for ligand affinity. The combination of 3D-QSAR and homology modeling proved successful for the interpretation of structure-affinity relationships as well as the validation of the individual modeling approaches.
authors.affiliation: NeuroSearch A/S, 93 Pederstrupvej, DK-2750 Ballerup, Denmark.
authors.forename: Karine
authors.initials: K
authors.lastname: Audouze
authors.forename: Elsebet Østergaard
authors.initials: EØ
authors.lastname: Nielsen
authors.forename: Gunnar M
authors.initials: GM
authors.lastname: Olsen
authors.forename: Philip
authors.initials: P
authors.lastname: Ahring
authors.forename: Tino Dyhring
authors.initials: TD
authors.lastname: Jørgensen
authors.forename: Dan
authors.initials: D
authors.lastname: Peters
authors.forename: Tommy
authors.initials: T
authors.lastname: Liljefors
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D006571:Heterocyclic Compounds; D008024:Ligands; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2