The actions of hallucinogens and structurally related compounds will be studied on 5-hydroxytryptamine (5-HT) binding sites and receptors, including those linked to adenylate cyclase in brain membranes and to the contraction of rabbit aorta (a receptor homologous with the 5-HT2 binding sites in brain membranes). With the methods of biochemical pharmacology, including thermodynamics and kinetics of binding, as well as radioautography (in vivo and in vitro) and smooth muscle pharmacology, the receptors and binding sites will be characterized and classified. Site-directed reagents will be used to identify the functional groups involved in the binding of 5-HT agonists and antagonists to the different sites. This information will be helpful in the classification, and also serves to probe the inferences from theoretical studies (done with the methods of quantum chemistry, macromolecular analysis, and molecular modeling), which are used to reveal the molecular properties and reactivity characteristics that determine recognition by 5-HT binding sites and activation of the receptors and that also determine the potency of hallucinogens. The molecular determinants leading from receptor recognition to receptor activation will be characterized from calculations with a proton transfer model (PTM) to obtain a three-dimensional molecular model for recognition and activation which will be probed by simulations with known agonists and antagonists. Computerized searches through crystallographical data banks will be used to identify PTM-like structures in protein and naturally occurring molecular arrangements that can be triggered by interaction with 5-HT analogs. New derivatives will be designed, synthesized and tested on the 5-HT sites to probe the resulting hypotheses and the predictions, and to investigate further the findings that affinities for the 5-HT sites and ability to activate the 5-HT receptors (as well as hallucinogenic activity) are altered by minor structural modifications. The integration of results from pharmacology, biochemistry, microscopic anatomy, organic chemistry, molecular modeling and theoretical chemistry will reveal the discrete determinants for the actions of the hallucinogenic compounds on 5-HT receptors and, pari passu, yield information on the localization and the nature of 5-HT receptors in brain. When eventually combined with results from similar studies on other receptors on which hallucinogens act, the aggregate of effects leading to hallucinations may be understood at the molecular level.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA001875-11
Application #
3207013
Study Section
(DABB)
Project Start
1977-09-01
Project End
1989-08-31
Budget Start
1987-09-30
Budget End
1988-08-31
Support Year
11
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Osman, R; Weinstein, H (1991) A mechanistic basis for design of selective agonists for 5-HT receptors. NIDA Res Monogr 112:21-42
Blandina, P; Goldfarb, J; Walcott, J et al. (1991) Serotonergic modulation of the release of endogenous norepinephrine from rat hypothalamic slices. J Pharmacol Exp Ther 256:341-7
Weinstein, H; Osman, R (1990) On the structural and mechanistic basis of function, classification, and ligand design for 5-HT receptors. Neuropsychopharmacology 3:397-409
Kline, T B; Nelson, D L; Namboodiri, K (1990) Novel [(diazomethyl)carbonyl]-1,2,3,4-tetrahydronaphthalene derivatives as potential photoaffinity ligands for the 5-HT1A receptor. J Med Chem 33:950-5
Clarke, W P; Maayani, S (1990) Estrogen effects on 5-HT1A receptors in hippocampal membranes from ovariectomized rats: functional and binding studies. Brain Res 518:287-91
Green, J P (1990) Pharmacological receptors: the need for a compendium of classification, nomenclature and structure. Trends Pharmacol Sci 11:13-6
Beck, S G; Clarke, W P; Goldfarb, J (1989) Chronic estrogen effects on 5-hydroxytryptamine-mediated responses in hippocampal pyramidal cells of female rats. Neurosci Lett 106:181-7
Blandina, P; Goldfarb, J; Craddock-Royal, B et al. (1989) Release of endogenous dopamine by stimulation of 5-hydroxytryptamine3 receptors in rat striatum. J Pharmacol Exp Ther 251:803-9
Clarke, W P; Goldfarb, J (1989) Estrogen enhances a 5-HT1A response in hippocampal slices from female rats. Eur J Pharmacol 160:195-7
Blandina, P; Knott, P J; Leung, L K et al. (1989) Stimulation of histamine H2 receptor in rat hypothalamus releases endogenous norepinephrine. J Pharmacol Exp Ther 249:44-51

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