TY - JOUR T1 - 2-Fluoro-3-(4-nitro-phenyl)deschloroepibatidine Is a Novel Potent Competitive Antagonist of Human Neuronal α4β2 nAChRs JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1945 LP - 1952 DO - 10.1124/mol.105.021782 VL - 69 IS - 6 AU - Galya R. Abdrakhmanova AU - M. Imad Damaj AU - F. Ivy Carroll AU - Billy R. Martin Y1 - 2006/06/01 UR - http://molpharm.aspetjournals.org/content/69/6/1945.abstract N2 - A patch-clamp technique in a whole-cell configuration was used to examine the functional activity of recently developed 2-fluoro-3-(substituted phenyl)deschloroepibatidine analogs on two major subtypes of neuronal nicotinic acetylcholine receptors (nAChRs), α4β2 and α3β4, that predominate in the central and peripheral nervous systems, respectively. These epibatidine analogs have been shown previously to possess high binding affinity to α4β2 but not to α7 nAChRs and to inhibit nicotine-induced analgesia in behavioral pain tests. The 2-fluoro-3-(4-nitro-phenyl)deschloroepibatidine (4-nitro-PFEB) exhibited the most pronounced antagonist activity among these analogs when tested electrophysiologically on α4β2 nAChRs. It inhibited acetylcholine (ACh)-induced currents in a concentration-dependent manner with an IC50 value of 0.1 μM and produced complete inhibition at ∼1 μM concentration. 4-Nitro-PFEB at 0.1 μM concentration produced a 4-fold rightward shift in the ACh concentration-response curve without altering maximum ACh-induced response. This inhibitory effect of 4-nitro-PFEB was voltage- and use-independent and was partially reversible at its 1 μM concentration. The rise and decay kinetics of ACh-induced currents was not altered in the presence of 4-nitro-PFEB. In contrast to α4β2 nAChRs, this compound did not affect α3β4 nAChR-mediated currents at ≤1 μM (IC50 ∼63.9 μM). Overall, these functional data agree with previous binding and behavioral findings and suggest collectively that 4-nitro-PFEB is the most effective and selective antagonist of α4β2 versus α3β4 and α7 nAChRs among the tested analogs, acting on α4β2 nAChR through a competitive mechanism with a potency 17-fold higher than that of dihydro-β-erythroidine. ER -