Defense Date


Document Type


Degree Name

Doctor of Philosophy


Pharmacology & Toxicology

First Advisor

Billy R. Martin


Antagonists have been crucial in the characterization of nicotine's pharmacology. Initial evidence for the existence of central nicotinic receptors was based on the fact that nicotine produced a number of behavioral effects that were antagonized by ganglionic blockers that crossed the blood-brain barrier, such as mecamylamine and pempidine. Although the mechanism of action of these compounds has been studied extensively in the periphery, little is known about their mechanisms of action in the brain. These compounds are thought to be noncompetitive antagonists due to the fact that they do not compete for agonist binding to brain homogenate in vitro. However, pharmacological evidence in support of noncompetitive antagonism is lacking.

Dose-response curves for nicotine were determined in the presence of various doses of pempidine for depression of spontaneous activity and antinociception in mice. Pempidine was found to shift the dose-response curves for these effects of nicotine in a manner consistent with noncompetitive antagonism. A number of mecamylamine analogs were investigated for antagonism of these central effects of nicotine as well. These studies revealed that the N-, 2-, and 3-methyls were crucial for optimal efficacy and potency and suggests that these compounds possess a specific mechanism of action, possibly involving a receptor. Furthermore, the structure-activity relationships for the mecamylamine analogs were found to be different than that previously reported for the agonists, suggesting that they do not act at the same site.

The binding of [3H]-L-nicotine and [3H]-pempidine was studied in vitro to mouse brain homogenate and in situ to rat brain slices. The in situ binding of [3H]-L-nicotine to rat brain slices was quantitated autoradiographically to discrete brain areas in the presence and absence of 1, 10 and 100 µM nicotine and pempidine. Pempidine did not effectively displace [3H]-L-nicotine binding. The studies with [3H]-pempidine failed to demonstrate saturable binding.

The evaluation of the antagonism of nicotine by mecamylamine and pempidine presented in this thesis supports a noncompetitive action of these compounds in the brain. The shift in the dose-response curves for nicotine, the structure-activity relationship for mecamylamine analogs and the binding studies are consistent with this hypothesis. The noncompetitive nature of these compounds suggests that they do not compete for the binding site of the agonist, and that endogenous nicotinic antagonists may exist in the brain.


Scanned, with permission from the author, from the original print version, which resides in University Archives.


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