This is a multidisciplinary proposal to continue our efforts to understand the structure-activity relationships of hallucinogens: drugs that are agonists at the serotonin 5-HT2A receptor. The work involves computer-assisted ligand design and receptor docking studies, both in vitro and in vivo pharmacology, and molecular biology methods.
Aims i n this application include an emphasis on the pharmacology and structure-activity relationships of LSD. There is an incomplete understanding of the factors that contribute to the uniquely high potency of LSD, and we propose several approaches to identify them. This effort will involve the synthesis and evaluation of several LSD analogues. We also have shown that the behavioral effects of LSD in rats occur in two temporal phases, and we will complete the synthesis of the 13-OH metabolite of LSD and assess its pharmacology and physiological relevance to these phases. We also shall continue efforts to characterize the basis for the behavioral changes induced by chronic LSD, and to search for targets other than the 5-HT2A receptor that may be important to the action of LSD.
Aim 2 is focused on developing improved homology models of the human 5- HT2A receptor, starting with the crystal structure of the ?2-adrenergic receptor. We shall have a focus on modeling extracellular loop 2, but also propose to examine the role of residue 3.36 in helix 3, as well as a previously-unrecognized disulfide linkage in extracellular loop 3. Computational approaches will be complemented by mutagenesis of loop residues and the use of stereochemically-defined lysergic acid amides.
A third aim proposes new agonist ligands that should have high affinity for the 5-HT2A receptor, but which should possess low affinity for the 5-HT2C receptor, based on an improved strategy from our molecular modeling efforts.
