Discovery of novel alpha7 nicotinic receptor antagonists.
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.
Peng
Youyi
Y
Intra-Cellular Therapies, Inc., New York, NY, 10032, United States.
Zhang
Qiang
Q
Snyder
Gretchen L
GL
Zhu
Hongwen
H
Yao
Wei
W
Tomesch
John
J
Papke
Roger L
RL
O'Callaghan
James P
JP
Welsh
William J
WJ
Wennogle
Lawrence P
LP
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
C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor