Pharmacological evaluation of the antagonism of nicotine's central effects by mecamylamine and pempidine.

The nature of mecamylamine's and pempidine's antagonism of nicotine in the central nervous system has not been defined clearly. Although these compounds are thought to be noncompetitive antagonists in the brain due to the fact that they do not compete effectively for agonist binding to brain tissue in vitro, pharmacological evidence is lacking. The alteration of nicotine's dose-response curves for depression of spontaneous activity and antinociception was determined in the presence of increasing concentrations of pempidine. Pempidine was found to increase the ED50 of nicotine (0.73 mg/kg) for depression of spontaneous activity in a dose-related manner. At a dose of 3 mg/kg, pempidine increased nicotine's ED50 4.7-fold. The maximum effect of nicotine was achieved in the presence of the highest dose of pempidine, suggesting competitive antagonism. However, pempidine did decrease the maximum effect of nicotine in producing antinociception at doses that increased the ED50 13.7-fold which suggests a noncompetitive action. The structural requirements for mecamylamine's antagonism of these nicotine effects was also determined in order to address the question of whether the antagonists are interacting at a receptor site. The structure-activity relationships of the mecamylamine analogs revealed that the N-, 2- and 3-methyl groups were important for optimal potency. Optical isomerism was found to have little effect on potency. Addition of pyridinyl groups to the nitrogen abolished the activity of these compounds. The structural requirements for the agonists and antagonists therefore appear to be quite different. The alterations produced similar results for antagonism of both effects of nicotine. Mecamylamine and pempidine therefore appear to exhibit both competitive and noncompetitive properties in antagonizing the central effects of nicotine.