Synthesis and binding affinities of 5-(3-pyridinyl)- and 5-(3-quinolinyl)-4-azahomoadamantanes to alpha7 nicotinic acetylcholine receptors.
A general synthetic route that can lead to nicotinic ligands bearing a variety of bulky aza-ring systems was developed. This methodology was applied to obtain 5-(3-pyridinyl)- and 5-(3-quinolinyl)-4-azahomoadamantanes 2a, 3a and 2b, 3b. The parent 5-(3-pyridinyl)-4-azahomoadamantane 2a (Ki = 5.0 microM) binds with about 100 times lower affinity than (+)-epibatidine 1 (Ki = 0.045 microM) to alpha7 nicotinic acetylcholine receptors (nAChRs). N-methyl substitution of 2a gives compound 3a which has about nine times lower binding affinity. The replacement of pyridinyl with a quinolinyl ring (compounds 2b, 3b) results in a dramatic reduction in potency (Ki > 1000 microM).
Tataridis
Dimitris
D
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Panepistimioupoli-Zografou, GR 15 771 Athens, Greece.
Kolocouris
Antonios
A
Fytas
George
G
Kolocouris
Nicolas
N
Foscolos
George B
GB
Poulas
Konstantinos
K
Tzartos
Socrates J
SJ
D000218:Adamantane / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002038:Bungarotoxins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000378:metabolism; D011485:Protein Binding; D011725:Pyridines / Q000378:metabolism; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D064569:alpha7 Nicotinic Acetylcholine Receptor
C476011:5-(3-pyridinyl)-4-azahomoadamantane; C476013:5-(3-quinolinyl)-4-azahomoadamantane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002038:Bungarotoxins; C579167:Chrna7 protein, human; D008024:Ligands; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C082748:epibatidine; D000218:Adamantane