Discovery of novel α7 nicotinic receptor antagonists

Two distinct families of small molecules were discovered as novel α7 nicotinic acetylcholine receptor (nAChR) antagonists by pharmacophore-based virtual screening. These novel antagonists exhibited selectivity for the neuronal α7 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.

Graphical abstractTwo distinct families of small molecules were discovered as novel selective α7 nicotinic acetylcholine receptor (nAChR) antagonists by pharmacophore-based virtual screening. These antagonists exhibited good brain penetration and neuroprotection in a mouse seizure-like behavior model induced by the nerve agent diisopropylfluorophosphate (DFP).Figure optionsDownload full-size imageDownload as PowerPoint slide