This project is designed to """"""""map"""""""" the three dimensional structure and electronic character of a series of cocaine analogs. The mapping will include the overall geometry of the drug molecules as well as the electronic characteristics defined by net atomic charges, electron density distribution, electrostatic potentials, and intermolecular interaction energies. To calculate these quantities, carefully measured experimental x-ray diffraction data will be collected on a selected set of cocaine analogs with various types of functional group substituents and varying degrees of pharmacological activity and receptor affinity. The specific compounds chosen for charge density analysis are: (1) (-)-2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane 1,5- naphthalenedisulfonate (WIN 35,428), a potent antagonist of the dopamine transporter which is 3-10 times more potent than (-)-cocaine as a psychomotor stimulant. (2) (-)-2beta-carboethoxy-3beta-benzoyloxytropane, an analog of cocaine that has been detected in the urine of simultaneous cocaine and ethanol abusers. (3) benzoylecgonine, a cocaine metabolite in which the 2beta-carbomethoxy substituent has been converted to a carboxylic acid substituent. (4) (-)-2beta-hydroxypropyl-3beta-phenyltropane, a recently synthesized WIN analog with very high affinity for the cocaine receptor (6-7 times more potent than cocaine). (5) (-)-2beta-prop-2-enoyl-3beta-phenyltropane methyl ester, a recently synthesized WIN analog with high affinity for the cocaine receptor (3-4 times more potent than cocaine). Using the results from the x-ray crystal structures of cocaine analogs not before determined, information regarding the three dimensional structure and conformation of the molecules will be obtained. These data will be used in an attempt to understand how small structural modifications can result in radical changes in pharmacological activity. To progress beyond a simple lock and key model, adding the electronic structure of the molecules determined experimentally from high resolution x-ray diffraction measurements allows a more complete description of the stereochemical, conformational, and electronic requirements of the cocaine receptor binding sites to be developed.
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