New ligands with affinity for the alpha4beta2 subtype of nicotinic acetylcholine receptors. Synthesis, receptor binding, and 3D-QSAR modeling.
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.
Audouze
Karine
K
NeuroSearch A/S, 93 Pederstrupvej, DK-2750 Ballerup, Denmark.
Nielsen
Elsebet Østergaard
EØ
Olsen
Gunnar M
GM
Ahring
Philip
P
Jørgensen
Tino Dyhring
TD
Peters
Dan
D
Liljefors
Tommy
T
Balle
Thomas
T
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*
D006571:Heterocyclic Compounds; D008024:Ligands; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2