Pharmacological properties and predicted binding mode of arylmethylene quinuclidine-like derivatives at the α3β4 nicotinic acetylcholine receptor (nAChR).
We have carried out a pharmacological evaluation of arylmethylene quinuclidine derivatives interactions with human α3β4 nAChRs subtype, using cell-based receptor binding, calcium-influx, electrophysiological patch-clamp assays and molecular modeling techniques. We have found that the compounds bind competitively to the α3β4 receptor with micromolar affinities and some of the compounds behave as non-competitive antagonists (compounds 1, 2 and 3), displaying submicromolar IC(50) values. These evidences suggest a mixed mode of action for these compounds, having interactions at the orthosteric site and more pronounced interactions at an allosteric site to block agonist effects. One of the compounds, 1-benzyl-3-(diphenylmethylene)-1-azoniabicyclo[2.2.2]octane chloride (compound 3), exhibited poorly reversible use-dependent block of α3β4 channels. We also found that removal of a phenyl group from compound 1 confers a partial agonism to the derived analog (compound 6). Introducing a hydrogen-bond acceptor into the 3-benzylidene quinuclidine derivative (compound 7) increases agonism potency at the α3β4 receptor subtype. Docking into the orthosteric binding site of a α3β4 protein structure derived by comparative modeling accurately predicted the experimentally-observed trend in binding affinity. Results supported the notion that binding requires a hydrogen bond formation between the ligand basic nitrogen and the backbone carbonyl oxygen atom of the conserved Trp-149.
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David C
DC
Kombo
Terry A
TA
Hauser
Vladimir P
VP
Grinevich
Matthew S
MS
Melvin
Jon-Paul
JP
Strachan
Serguei S
SS
Sidach
Joseph
J
Chewning
Nikolai
N
Fedorov
Kartik
K
Tallapragada
Scott R
SR
Breining
Craig H
CH
Miller
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011812:Quinuclidines / Q000737:chemistry* / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D011812:Quinuclidines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4