Pharmacological properties and predicted binding mode of arylmethylene quinuclidine-like derivatives at the ¦Á3¦Â4 nicotinic acetylcholine receptor (nAChR)
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- 作者：David C. Kombo ; david.kombo@targacept.com ; dckombo777@mail.com ; Terry A. Hauser ; Vladimir P. Grinevich ; Matthew S. Melvin ; Jon-Paul Strachan ; Serguei S. Sidach ; Joseph Chewning ; Nikolai Fedorov ; Kartik Tallapragada ; Scott R. Breining ; Craig H. Miller
- 关键词：ACHBP ; acetylcholine-binding protein ; Ach ; acetylcholine ; CNS ; central nervous system ; MEC ; minimum-effective concentration ; nAChR ; nicotinic acetylcholine receptor ; NIC ; nicotine ; Pdb ; protein databank ; rmsd ; root-mean-squared-deviation ; ROC ; receiver op
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：1 March, 2013
- 年：2013
- 卷：23
- 期：5
- 页码：1450-1455
- 全文大小：485 K
文摘
We have carried out a pharmacological evaluation of arylmethylene quinuclidine derivatives interactions with human ¦Á3¦Â4 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 ¦Á3¦Â4 receptor with micromolar affinities and some of the compounds behave as non-competitive antagonists (compounds 1, 2 and 3), displaying submicromolar IC50 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 ¦Á3¦Â4 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 ¦Á3¦Â4 receptor subtype. Docking into the orthosteric binding site of a ¦Á3¦Â4 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.