The major aims of this proposal are all focused on the serotonin 5-HT2A receptor, which is now being seen as a critical site for normal cognitive function and as a target for a typical antipsychotic agents. In the first aim, the PI will study how the oxygen substitution patterns in phenethylamine type 5-HT2A agonists affect orientation of the oxygen atom unshared electrons, which are clearly determinants of ligand recognition and activation. This information is critical to developing a 3D pharmacophore that can encompass all of the phenethylamine agonists possessing different substitution patterns.
This aim will be accomplished by the synthesis of a variety of rigid analogues wherein the oxygen function is tethered into a ring of varying size, that forces the oxygen atom to adopt a particular conformation. Target molecules will be evaluated for both affinity and efficacy at the cloned rat 5-HT2a receptor, and will also be assessed for specificity at the cloned human 5-HT2A, 5-HT2B and 5-HT2C receptors through a collaborative effort.
The second aim i s directed toward a study of the hypothesis that the late phases of LSD intoxication may resemble certain aspects of paranoid psychosis, a suggestion made by D.X. Freedman. In particular, we hypothesize that the initial 5-HT2A stimulatory effect of LSD sensitizes brain dopamine pathways to the effect of a potent dopaminergic metabolite, 13-hydroxy-LSD, which may accumulate during the action of LSD, and that this metabolite plays a key role in the psychopharmacology of the second temporal phase of LSD intoxication. These studies would have relevance to understanding possible roles of the 5-HT2A receptor in psychosis and schizophrenia. Major effort in this aim will be directed toward the synthesis and characterization of 13-hydroxy ergolines, using new approaches for construction of the ergoline nucleus. Drug discrimination studies will be employed to examine the nature of the LSD cue, as a function of time after administration, with a particular emphasis on the possibility that dopaminergic effects will predominate in the interoceptive cue at later times after LSD administration.
The third aim i s directed toward the synthesis of new, extremely potent (subnanomolar), agonist ligand for the 5-HT2 family of receptors. The initial target will be a molecule that can be tritiated to provide a radioligand with very high affinity and relatively high specific activity.
A fourth aim i s directed toward further examination of the effect of ring-fluorination on receptor selectivity of tryptamines. In particular, these studies are directed toward the preparation of new 5-HT1A receptor selective agonists.
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