Characterization of nicotine binding to the rat brain P/sub 2/ preparation: the identification of multiple binding sites which include specific up-regulatory site(s)

Thesis/Dissertation · Sun Jan 01 00:00:00 EST 1984

OSTI ID:5021036

Sloan, J W

These studies show that nicotine binds to the rat brain P/sub 2/ preparation by saturable and reversible processes. Multiple binding sites were revealed by the configuration of saturation, kinetic and Scatchard plots. A least squares best fit of Scatchard data using nonlinear curve fitting programs confirmed the presence of a very high affinity site, an up-regulatory site, a high affinity site and one or two low affinity sites. Stereospecificity was demonstrated for the up-regulatory site where (+)-nicotine was more effective and for the high affinity site where (-)-nicotine had a higher affinity. Drugs which selectively up-regulate nicotine binding site(s) have been identified. Further, separate very high and high affinity sites were identified for (-)- and (+)-(/sup 3/H)nicotine, based on evidence that the site density for the (-)-isomer is 10 times greater than that for the (+)-isomer at these sites. Enhanced nicotine binding has been shown to be a statistically significant phenomenon which appears to be a consequence of drugs binding to specific site(s) which up-regulate binding at other site(s). Although Scatchard and Hill plots indicate positive cooperatively, up-regulation more adequately describes the function of these site(s). A separate up-regulatory site is suggested by the following: (1) Drugs vary markedly in their ability to up-regulate binding. (2) Both the affinity and the degree of up-regulation can be altered by structural changes in ligands. (3) Drugs with specificity for up-regulation have been identified. (4) Some drugs enhance binding in a dose-related manner. (5) Competition studies employing cold (-)- and (+)-nicotine against (-)- and (+)-(/sup 3/H)nicotine show that the isomers bind to separate sites which up-regulate binding at the (-)- and (+)-nicotine high affinity sites and in this regard (+)-nicotine is more specific and efficacious than (-)-nicotine.

• Research Organization: Kentucky Univ., Lexington (USA)
• OSTI ID: 5021036
• Resource Relation: Other Information: Thesis (Ph. D.)
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
NICOTINE
CHEMICAL BONDS
AFFINITY
BIOCHEMICAL REACTION KINETICS
BRAIN
DOSE-RESPONSE RELATIONSHIPS
ISOMERS
LEAST SQUARE FIT
LIGANDS
RATS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
ALKALOIDS
AMINES
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
AZINES
AZOLES
BODY
CENTRAL NERVOUS SYSTEM
DRUGS
HETEROCYCLIC COMPOUNDS
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
MAMMALS
MAXIMUM-LIKELIHOOD FIT
NERVOUS SYSTEM
NUMERICAL SOLUTION
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PARASYMPATHOLYTICS
PARASYMPATHOMIMETICS
PYRIDINES
PYRROLES
PYRROLIDINES
REACTION KINETICS
RODENTS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques