Tetrakis-azaaromatic quaternary ammonium salts: Novel subtype-selective antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release

A series of tetrakis-azaaromatic quaternary ammonium salts was synthesized to identify compounds with higher affinity and selectivity as antagonists at neuronal nicotinic receptor subtypes (nAChR) that mediate nicotine-evoked DA release. A high hit rate was achieved in identifying potent analogs that inhibit these nAChRs. Three tetrakis analogs, 11j, 11f, and 11g, were identified as potent (IC50 = 3, 28 and 56 nM, respectively) antagonists at these receptors. These compounds represent a novel structural class of nicotinic receptor antagonists.

Graphical abstractTetrakis-azaaromatic quaternary ammonium salts were identified as antagonists with high affinity and selectivity at nAChR subtypes (nAChR) that mediate nicotine-evoked DA release. Analog 11j (IC50 = 3 nM), is a representative member of this novel structural class of selective nicotinic receptor antagonists.Figure optionsDownload full-size imageDownload as PowerPoint slide