This application is a component of an Interactive Research Project Grant (IRPG) composed of four interrelated projects (including: Sealfon, PI, Maayani, PI. and Martinelli, PI) aimed at understanding the mechanisms of action of hallucinogenic drugs of abuse at the cellular/molecular level of detail. The common underlying hypothesis is that the hallucinogenic potential of certain compounds reflects specific, identifiable differences from congeneric non-hallucinogens in the molecular mechanisms of ligand/receptor interaction and in the structural and dynamic response of the receptors to these interactions (e.g., as reflected in the ensuing effector-coupling and desensitization mechanisms). This hypothesis leads to the proposed investigations of the molecular details of the discriminant factors responsible for the special properties underlying the actions of hallucinogenic drugs of abuse. The collaborative efforts include structure-function explorations by modifications of the same set of specific 5-HT receptors on which hallucinogenic molecules act, and coordinated assessments of discriminant pharmacological characteristics and interactions of hallucinogens. To achieve the goals of the theoretical components of this IRPG the following interrelated steps will be taken: 1. We will construct complete three dimensional molecular models of the 5-HT2 and 5-HT1C receptors and their complexes with hallucinogens and non- hallucinogens. 2. We will simulate the dynamics of ligand/receptor complexes with the models of the 5-HT2 and 5-HT1C receptors in order to examine the time-dependent elements of the receptor recognition process for agonist vs. antagonist pairs, and hallucinogen vs. non-hallucinogen pairs, and in order to identify the time-dependent changes in receptor structure related to the signal transduction mechanisms induced by the various pairs of compounds. 3. We will explore with computational modeling and dynamic simulation the structural basis for the special interaction properties of the 5-HT6 receptor with hallucinogenic compounds in the class of """"""""tricyclic psychotropic drugs"""""""" for which it was shown to have high affinity, and with structurally cognate nonhallucinogens. Structure- function relations of both the ligands and the receptors will be explored in the theoretical constructs and, in parallel, experimentally. Mutant receptor constructs and pharmacological assays suggested by the results of the computational studies will be performed in the proposed shared Core facilities of the IRPG. In addition, proposed collaborative studies will take advantage of the insights developed from the receptor models and computational simulations to study directly the mechanistic basis of any pharmacologically defined discrimination between the actions of hallucinogens and structurally related non-hallucinogens on the receptors, including the structural determinants (of the receptors and of the ligands), as well as measurable consequences of receptor/effector coupling (e.g., relative efficacy and desensitization) and the mechanisms of cross- amplification of the actions of various receptor/effector systems.
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