title: Discovery of novel alpha7 nicotinic receptor antagonists.
abstract: Two distinct families of small molecules were discovered as novel alpha7 nicotinic acetylcholine receptor (nAChR) antagonists by pharmacophore-based virtual screening. These novel antagonists exhibited selectivity for the neuronal alpha7 subtype over other nAChRs and good brain penetration. Neuroprotection was demonstrated by representative compounds 7i and 8 in a mouse seizure-like behavior model induced by the nerve agent diisopropylfluorophosphate (DFP). These novel nAChR antagonists have potential use as antidote for organophosphorus nerve agent intoxication.
authors.affiliation: Intra-Cellular Therapies, Inc., New York, NY, 10032, United States.
authors.forename: Youyi
authors.initials: Y
authors.lastname: Peng
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Snyder
authors.forename: Hongwen
authors.initials: H
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.forename: John
authors.initials: J
authors.lastname: Tomesch
authors.forename: Roger L
authors.initials: RL
authors.lastname: Papke
authors.forename: James P
authors.initials: JP
authors.lastname: O'Callaghan
authors.forename: William J
authors.initials: WJ
authors.lastname: Welsh
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Wennogle
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D003198:Computer Simulation; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D018733:Nicotinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D011485:Protein Binding; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor