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 (IC(50)=3, 28 and 56nM, respectively) antagonists at these receptors. These compounds represent a novel structural class of nicotinic receptor antagonists.
Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536-0082, USA.
Zhenfa
Z
Zhang
Guangrong
G
Zheng
Marharyta
M
Pivavarchyk
A Gabriela
AG
Deaciuc
Linda P
LP
Dwoskin
Peter A
PA
Crooks
D001372:Aza Compounds / Q000737:chemistry*; D004298:Dopamine / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology*; D012492:Salts
D001372:Aza Compounds; D018733:Nicotinic Antagonists; D000644:Quaternary Ammonium Compounds; D012492:Salts; D009538:Nicotine; D004298:Dopamine