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    Structure-activity relationship of cocaine analogs: The synthesis of 3-beta-substituted cocaine analogs and computer-aided prediction of the pharmacological activity of cocaine analogs

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    Author
    Yang, Biao
    Advisor
    Wright, Jeremy, Ph.D.
    Date
    1994
    Type
    dissertation
    
    Metadata
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    Abstract
    Ten 3{dollar}\beta{dollar}-ecgonine analogs were synthesized and characterized by {dollar}\sp1{dollar}H and {dollar}\sp{lcub}13{rcub}{dollar}C NMR, MS and elemental analysis. The compounds were synthesized as ({dollar}-{dollar})-stereoisomers from ({dollar}-{dollar})-cocaine. These compounds were assessed for their ability to inhibit ({dollar}\sp3{dollar}H) cocaine binding to rat striatal tissue and to inhibit ({dollar}\sp3{dollar}H) dopamine uptake into rat striatal synaptosomes. In this series of compounds, the length of the spacer between the aryl group and the tropane skeleton ranged from 1 to 4 bond distances, and conformational flexibility of the linkage and orientation of the aryl ring system were controlled by various types of linkage. The results showed that the potencies of these 3{dollar}\beta{dollar} substituted ecgonine methyl esters were acutely sensitive to the distance between the aryl ring and the tropane skeleton and to the orientation of the aryl ring system. The most potent of the analogs was (1R-2-exo-3-exo)-2-(carbomethoxy)-8-methyl-8-azabicyclo (3.2.1) octyl 3-{dollar}\beta{dollar}-styrene. One of the less potent compounds was found to inhibit ({dollar}\sp3{dollar}H) cocaine binding and ({dollar}\sp3{dollar}H) dopamine uptake by a mechanism apparently different from that of the nine other analogs. The current study provided a clearer picture of the shape and size of the putative hydrophobic binding pocket at the cocaine receptor. Conformational properties of cocaine, WIN 32 065-2 and the WIN vinyl analog were studied via Austin Model 1 (AM1) semi-empirical calculations. The conformational space of the molecules, as defined by the dihedral angles representing the orientation of the 2{dollar}\beta{dollar} and 3{dollar}\beta{dollar} sidechains, was calculated on a 13 x 13 grid in the gas phase and included full geometry optimization at each grid point. Aqueous solvation free energy surfaces were obtained using the AM1-Solvation Model 2 (AM1-SM2). The lowest energy points from the surfaces were fully optimized in both the gas and aqueous phases. Results predict the minimum 2{dollar}\beta{dollar} and 3{dollar}\beta{dollar} sidechain conformations to be similar between the gas and aqueous phases, between the neutral and protonated forms of the molecules and between the three molecules. A detailed analysis of the relationship of structural contributions to changes in conformational properties is presented. Population analysis of the minimum energy regions indicates the neutral forms of WIN and the WIN vinyl analog to be more conformationally restricted than cocaine. This conformational restriction is related to steric interactions between the 2{dollar}\beta{dollar} and 3{dollar}\beta{dollar} moieties of the WIN compounds. Cocaine is calculated to be more favorably solvated than the WIN compounds due to the presence of the ester groups in the 2{dollar}\beta{dollar} and 3{dollar}\beta{dollar} moieties. The calculations predict the pK{dollar}\sb{lcub}\rm a{rcub}{dollar}s of the tropane nitrogen of the WIN compounds to be higher than in cocaine. A model is presented relating the decreased conformational flexibility, decreased aqueous solvation and increased pK{dollar}\sb{lcub}\rm a{rcub}{dollar}s of the WIN compounds to their increased binding affinity to the cocaine receptor. The present results suggest that both the protonated form and the neutral form of the compounds may bind with high affinity to the cocaine receptor. The binding of either form of the drugs could not be eliminated based on the current study. (Abstract shortened by UMI.)
    Description
    University of Maryland, Baltimore. Pharmaceutical Sciences. Ph.D. 1994
    Keyword
    Chemistry, Organic
    Chemistry, Pharmaceutical
    Health Sciences, Pharmacy
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/1586
    Collections
    Theses and Dissertations All Schools
    Theses and Dissertations School of Pharmacy

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