This is a comprehensive medicinal chemistry proposal, integrating a number of synthetic organic chemistry projects with pharmacological assessment, all in the same laboratory. The major short-term goals are two-fold. One is to develop compounds that will be used to elucidate the mechanism of action of hallucinogenic drugs such as LSD. The other is to continue the development of molecular probes of serotonin receptor sub-types. Both of these goals relate to the long term objective of achieving a greater understanding of the neuronal substrates underlying the action of a major class of drugs of abuse, as well as gaining a better appreciation for the roles of certain classes of monoamine receptors in the regulation of behavior and psychopathologies such as schizophrenia.
The specific aims of the proposal focus on several classes of molecules that have the potential to possess hallucinogenic activity and to be useful probes of the binding domains of serotonin and dopamine receptors. Particular structures to be studied include tryptamine analogs with conformationally constrained side chains, and isomeric 2,4-dimethylazetidines in place of N,N-dialkyl groups; 6-fluorinated tryptamine derivatives; a side- chain rigidified analogue of a potent phenethylamine 5-HT2A agonist; two mescaline congeners where the methoxy groups have been constrained into dihydrofuran rings; and two isomeric thienopyrrole analogues of hallucinogenic tryptamines. New compounds will be assessed in the Principal Investigator's laboratory using the two-lever drug discrimination assay in rats trained to discriminate saline from LSD tartrate and selected other drugs. This will give an in vivo measure of """"""""LSD-like"""""""" behavioral activity. The Principal Investigator's laboratory will also carry out radioligand competition assays on new molecules to assess their affinity for the 5-HT 1A, 1B, 1D, 2A and 2C serotonin receptor subtypes. In some cases adrenergic and dopaminergic receptor affinities will also be examined. Collaborators have been enlisted at other laboratories who will carry out more detailed examinations in cloned serotonin and dopamine receptors, and who will also determine functional efficacies of interesting new molecules. It is anticipated that correlations between the in vitro and in vivo results can be made that will bear on the mechanism(s) of action of hallucinogenic drugs. The results will also be integrated to allow inferences about the topography of the binding domains of the relevant receptors, and to allow conclusions to be made regarding which portions of the molecules are important for binding and receptor activation.
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