This is a highly interdisciplinary proposal to continue our efforts to understand the structure-activity relationships of hallucinogens: drugs that are agonists at the serotonin 5-HT2A receptor. It involves computer-assisted ligand design and receptor docking studies, in vitro and in vivo pharmacology, and molecular biology methods. More specifically, it builds on a recent homology model of the serotonin 5-HT2A receptor that we have developed in our laboratory, and proposes a number of specific mutations within the putative ligand binding domain. These mutations will be combined with pharmacological assessment of small agonist ligands to be synthesized or already in our extensive library, in order to examine functional complementation of binding and activation, the most powerful technique presently available for identification of direct ligand contacts within a receptor. Conformationally-constrained phenethylamine ligands also have been designed specifically to probe the relationship between the conformation of the aminoethyl side chain and the aromatic ring in agonist-receptor interactions. In addition, a strategy is also proposed to develop an agonist ligand that should have high affinity for the 5-HT2A receptor, but which should possess low affinity for the 5-HT2c receptor. A short series of derivatives of a novel template we have recently developed with high affinity for the serotonin 5-HT1A receptor is also proposed and, along with known agonist ligands for this receptor, a homology model for the 5-HT1A receptor will be refined using methods similar to those we used for the 5-HT2A receptor. Finally, we shall continue our investigations into the nature of the biphasic action of the potent hallucinogenic agent LSD, where we have discovered that the effects of LSD in rats are mediated initially by activation of 5-HT2A receptors, but in a later temporal phase dopamine systems appear to be activated. In addition, we shall study the underlying basis for the behavioral sensitization that occurs following long-term LSD administration to rats. These studies will involve examination of a number of antipsychotic drugs to determine whether they can attenuate or block LSD-induced behavioral sensitization in rats either acutely, or following continuous administration. We also propose the synthesis of a 13-hydroxyergoline as a potential dopaminergic compound, to assess the potential dopaminergic activity of the 13-hydroxy metabolite of LSD. These studies may lead to a rat model of schizophrenia that could be very useful in developing and understanding new types of antipsychotic agents.
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