X-ray data for a series of neuroleptic drug molecules and their metabolites will be collected in order to determine the three- dimensional structure and to """"""""map"""""""" the electronic character of these molecules. These data will be used in an attempt to understand how small structural modifications may result in radical differences in antipsychotic activity. First simple synthetic methods will be used to obtain the metabolites from the parent compounds. Then, high resolution single crystal x-ray diffraction measurements will be used to calculate the net atomic charges, electrostatic potentials (EP) and electron density distributions (EDD). These quantities will be used to predict relative pharmacological activities within the series of molecules. Initially a selected set of tricyclic neuroleptics resulting from various metabolic pathways was chosen for study. These include a parent compound, sulfoxide metabolite, monodesmethyl metabolite, didesmethyl metabolite and ring hydroxide. These studies will be used to identify EDD, MEP and net atomic charge trends that may be used to predict relative reactivities. Information will also be available concerning the stereochemical and conformational requirements of the dopamine receptor site.
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