This proposal outlines the synthesis and evaluation of a variety of isomers and bioisosteres of hallucinogen analogues. All these represent chemical structures where the conformational flexibility or stereochemistry has been fixed, so that analysis of structure- activity relationships will be facilitated. Particular compounds of interest to be examined include lysergic acid amides of the isomers of 2,4-dimethylazetidine and 2,5-dimethylpyrrolidine, substituted trans-indol-3-ylcyclopropylamine and certain benzofuran and 2,3-dihydrobenzofuran bioisosteres of the hallucinogenic tryptamines and amphetamines. Receptor binding profiles will be examined for each of the series, for affinity at a variety of serotonin receptor subtypes, and for the lysergic acid amides at dopamine D-l and D-2 receptors. Ability to stimulate inositol triphosphate turnover will be used to assess agonist/antagonist activity in the series. The two-lever drug discrimination paradigm will be used as a measure of in vivo hallucinogen potency, utilizing rats trained to discriminate saline from LSD. Other training drugs may be used in this paradigm, where appropriate, as in vivo correlates to observed in vivo results. Molecular mechanics procedures will be used to model the conformational mobility and preferred conformations in these series.
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