title: Novel potent ligands for the central nicotinic acetylcholine receptor: synthesis, receptor binding, and 3D-QSAR analysis.
abstract: In the past few years the focus on central acetylcholine receptors has shifted from compounds with affinity for muscarinic acetylcholine receptors (mAChR) to compounds with affinity for nicotinic acetylcholine receptors (nAChR). The therapeutic potential includes treatment of a variety of diseases, e.g., Alzheimer's disease, Parkinson's disease, and Tourette's syndrome. This work describes the synthesis of six novel series of potent ligands with nanomolar affinity for the alpha4beta2 nAChR subtype. Structure-activity relationship (SAR) was evaluated by the calculation of a 3D-QSAR model. 3D-QSAR analysis of the compounds using the GRID/GOLPE methodology resulted in a model of high quality (R(2) = 0.97, Q(2) = 0.81). The coefficient plots reveal that the steric interactions between the target and our compounds are of major importance for the affinity. Bulky substituents in the 6-position of the pyridine ring will reduce the affinity of the compounds, whereas bulky ring systems including a sp(3)-nitrogen will increase the affinity of the compounds.
authors.affiliation: NeuroSearch A/S, 93 Pederstrupvej, DK-2750 Ballerup, Denmark.
authors.forename: S F
authors.initials: SF
authors.lastname: Nielsen
authors.forename: E O
authors.initials: EO
authors.lastname: Nielsen
authors.forename: G M
authors.initials: GM
authors.lastname: Olsen
authors.forename: T
authors.initials: T
authors.lastname: Liljefors
authors.forename: D
authors.initials: D
authors.lastname: Peters
mesh_terms: D000470:Alkaloids / Q000378:metabolism; D000818:Animals; D001392:Azocines; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018678:Cholinergic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008968:Molecular Conformation; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism; D011807:Quinolizines; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D014316:Tritium; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D001392:Azocines; D018678:Cholinergic Agents; D008024:Ligands; D020033:Protein Isoforms; D011807:Quinolizines; D011978:Receptors, Nicotinic; D014316:Tritium; C004712:cytisine; D000093843:Quinolizidine Alkaloids