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 usin...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-06, Vol.49 (11), p.3159-3171
Main Authors: Audouze, Karine, Nielsen, Elsebet Østergaard, Olsen, Gunnar M, Ahring, Philip, Jørgensen, Tino Dyhring, Peters, Dan, Liljefors, Tommy, Balle, Thomas
Format: Article
Language:English
Subjects:
Animals
Cerebral Cortex - metabolism
Heterocyclic Compounds - chemistry
Hydrogen Bonding
In Vitro Techniques
Ligands
Male
Models, Molecular
Molecular Conformation
Quantitative Structure-Activity Relationship
Radioligand Assay
Rats
Rats, Wistar
Receptors, Nicotinic - chemistry
Receptors, Nicotinic - metabolism
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Summary: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.
ISSN:0022-2623