8-week randomised, active treatment with twice-daily TC-5214 (dexmecamylamine) (0.5, 2 or 4 mg in Study 004; 0.1, 1 or 4 mg in Study 005) or placebo

To determine whether the high-sensitivity (HS) and low-sensitivity (LS) isoforms of the human α4β2 neuronal nicotinic receptors (NNRs) components display differences in their pharmacological profiles with respect to mecamylamine sensitivity, it was conducted nicotine concentration-response studies in the absence or presence of either of the enantiomers, TC-5214 (dexmecamylamine) or TC-5213. The analysis indicated that the relationship between inhibition of peak current produced by 1 μM TC-5214, and nicotine concentration was not linear. Responses induced by concentrations of nicotine up to 1 μM (primarily reflecting HS activation) were not appreciably inhibited by TC-5214. In comparison, responses to concentrations of nicotine greater than 1 μM (primarily reflecting LS activation) were profoundly inhibited. Increasing the concentration of TC-5214 to 2 μM resulted in a more complete and nonselective inhibition of responses at all nicotine concentrations applied. These results suggest that at low concentrations, TC-5214 preferentially inhibits LS α4β2 receptors. TC-5213 also inhibited responses to relatively high concentrations of nicotine (10 μM), but this effect was not found to be statistically significant.