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

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 EC(50)s of 0.012 muM (72% efficacy) and 0.027 muM (81% efficacy) at alpha4beta2 and alpha3beta4 nAChRs, respectively, but was full at alpha7 nAChRs with an EC(50) of 4.8 muM. Testing of the analog at different concentrations revealed that it acts as a full agonist with an EC(50) of 0.36 muM at alpha4beta2 nAChRs and induces partial agonist effect (66% efficacy) at alpha7 nAChRs with an EC(50) of 9.8 muM and an IC(50) corresponding to 225 muM. In contrast, the analog caused only 24% maximal activation at the range of concentrations from 0.1 to 100 muM and, in addition, induced an inhibition of alpha3beta4 nAChR function with an IC(50) of 8.3 muM. 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