Evaluation of the antagonism of nicotine by mecamylamine and pempidine in the brain
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. 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 ({sup 3} H)-L-nicotine and ({sup 3}H)-pempidine was studied in vitro to mouse brain homogentate and in situ to rat brain slices. The in situ binding of ({sup 3}H)-L-nicotine to rat brain slices was quantitated autoradiographically to discrete brain areas in the presence and absence of 1, 10 and 100 {mu}M nicotine and pempidine. Pempidine did not effectively displace ({sup 3}H)-L-nicotine binding.
- Research Organization:
- Virginia Commonwealth Univ., Richmond, VA (USA)
- OSTI ID:
- 5527069
- Resource Relation:
- Other Information: Thesis (Ph. D.)
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
AMINES
BIOCHEMICAL REACTION KINETICS
NICOTINE
RECEPTORS
AUTORADIOGRAPHY
BLOOD-BRAIN BARRIER
BRAIN
DOSE-RESPONSE RELATIONSHIPS
MICE
PHARMACOLOGY
RATS
TRITIUM COMPOUNDS
ALKALOIDS
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
AZINES
AZOLES
BODY
CENTRAL NERVOUS SYSTEM
DRUGS
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
KINETICS
MAMMALS
MEMBRANE PROTEINS
NERVOUS SYSTEM
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PARASYMPATHOLYTICS
PARASYMPATHOMIMETICS
PROTEINS
PYRIDINES
PYRROLES
PYRROLIDINES
REACTION KINETICS
RODENTS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques