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.
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