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.2008 Dec;55(8):1287-92.
doi: 10.1016/j.neuropharm.2008.08.007. Epub 2008 Aug 15.

3'-Fluoro substitution in the pyridine ring of epibatidine improves selectivity and efficacy for alpha4beta2 versus alpha3beta4 nAChRs

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3'-Fluoro substitution in the pyridine ring of epibatidine improves selectivity and efficacy for alpha4beta2 versus alpha3beta4 nAChRs

Galya R Abdrakhmanova et al. Neuropharmacology.2008 Dec.

Abstract

The analog of epibatidine having a fluoro substituent at the 3' position of the pyridine ring has been recently developed and shown to possess binding affinity in the pM range to alpha4beta2 nAChRs and in the nM range to alpha7 nAChRs and to exhibit potent agonist activity in nicotine-induced analgesia tests. Here we used patch-clamp technique in a whole-cell configuration to compare functional activity of 3'-fluoroepibatidine to that of epibatidine by itself on recombinant alpha4beta2, alpha7 and alpha3beta4 neuronal nAChRs. The agonist effect of (+/-)-epibatidine was partial and yielded comparable EC50s of 0.012 microM (72% efficacy) and 0.027 microM (81% efficacy) at alpha4beta2 and alpha3beta4 nAChRs, respectively, but was full at alpha7 nAChRs with an EC50 of 4.8 muM. Testing of the analog at different concentrations revealed that it acts as a full agonist with an EC50 of 0.36 microM at alpha4beta2 nAChRs and induces partial agonist effect (66% efficacy) at alpha7 nAChRs with an EC50 of 9.8 microM and an IC50 corresponding to 225 microM. In contrast, the analog caused only 24% maximal activation at the range of concentrations from 0.1 to 100 microM and, in addition, induced an inhibition of alpha3beta4 nAChR function with an IC50 of 8.3 microM. Our functional data, which are in agreement with previous binding and behavioral findings, demonstrate that 3'-fluoro substitution in the pyridine ring of epibatidine results in an improved pharmacological profile as observed by an increased efficacy and selectivity for alpha4beta2 versus alpha3beta4 nAChRs.

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Figures

Figure 1
Figure 1
Structure of epibatidine and 3’-fluoroepibatidine (RTI-31).
Figure 2
Figure 2
Agonist activity of (±)-epibatidine in α4β2, α7 and α3β4 nAChRs. A, Representative superimposed currents traces were induced by the application of 1mM ACh and (±)-epibatidine at concentrations that caused about a half activation relative to the ACh response in individual cells expressing indicated nAChR subtype and held at −80 mV. B, Dose-response curves for the peak currents induced by (±)-epibatidine in α4β2 (▽), α7 (□) and α3β4 (■) nAChRs. Peak currents induced by (±)-epibatidine at different concentrations were normalized to the peak current induced by ACh at 1mM concentration in each cell. Each symbol represents the mean ± S.E.M. The continuous curves represent a fit to Hill equation. Holding potential was −80 mV.
Figure 3
Figure 3
Analysis of the agonist activity of the 3’-fluoroepibatidine in α4β2, α7 and α3β4 nAChRs. A, Dose-response curves for the peak currents induced by the analog in α4β2 (■), α7 (▲) and α3β4 (●) nAChRs. Peak currents induced by the analog at different concentrations were normalized to the peak current induced by ACh at 1mM concentration in each tested cell. Each symbol represents the mean ± S.E.M. The continuous curves represent a fit to Hill equation. B, Representative superimposed current traces were induced by the application of 1mM ACh and the analog at 10 µM concentration in individual cells expressing an indicated nAChR subtype and held at −80 mV. Time constants of the decay (τ) correspond to 26.91 and 38.94 ms in the presence of 1 mM ACh and 10 µM 3’-fluoro analog, respectively, in the representative cell expressing nAChRs. C, Inhibition of 3’-fluoroepibatidine-induced currents in three representative cells expressing α4β2, α7 and α3β4 nAChRs by DHβE, MLA and mecamylamine, respectively. No response was induced by 3’-fluoroepibatidine in nontransfected SH-EP1 and HEK 293 cells. Holding potential was −80 mV.
Figure 4
Figure 4
Analysis of the antagonist activity of the 3’-fluoroepibatidine in α3β4 and α7 nAChRs. A, Concentration-response relationships for the analog constructed in α3β4 (■) and α7 (□) nAChRs. The peak amplitude of ACh (EC50)-evoked currents was taken in each cell to normalize the peak amplitude of the currents that were evoked in the presence of the analog at different concentrations. The curves were fitted to Hill equation. Symbols and bars represent the mean ± S.E.M. B, Examples of inhibitory effect of 3’-fluoro substituted analog on ACh(EC50)-induced currents in cells expressing α7 (top) and α3β4 (bottom) at concentration close to the determined IC50 value. Holding potential in A and B was −80 mV.
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References

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