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2-Fluoro-3-(4-nitro-phenyl)deschloroepibatidine Is a Novel Potent Competitive Antagonist of Human Neuronal 42 nAChRs

Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (G.R.A., M.I.D., B.R.M.); and Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina (F.I.C.)

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), 42 and 34, that predominate in the central and peripheral nervous systems, respectively. These epibatidine analogs have been shown previously to possess high binding affinity to 42 but not to 7 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 42 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 42 nAChRs, this compound did not affect 34 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 42 versus 34 and 7 nAChRs among the tested analogs, acting on 42 nAChR through a competitive mechanism with a potency 17-fold higher than that of dihydro--erythroidine.

Address correspondence to: Dr. Galya Abdrakhmanova, Assistant Professor, Department of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 E. Clay Street, P.O. Box 980524, Richmond, VA 23298. E-mail: gabdrakhmano{at}mail1.vcu.edu