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Conformational Analysis, Molecular Modeling, and Quantitative Structure–Activity Relationship Studies of Agents for the Inhibition of Astrocytic Chloride Transport

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Abstract

Molecular modeling studies were carried out on a series of 1-oxoisoindolines which are pharmacologically active as inhibitors of astrocytic chloride transport. Conformational analysis revealed that the halogen substituent exerted a pronounced steric directing effect on the acid side chain. The 4-substituted analogs apparently provided for the best spatial arrangement of pharamacophoric elements of the molecules. Conventional quantitative structure-activity relationship (QSAR) studies using lipophilic and dipole moment characteristics of the molecules as physical descriptor variables in the regression equation yielded a statistically significant model. Comparative molecular field analysis (CoMFA) was utilized as a three-dimensional QSAR technique to explore changes in the steric and electrostatic fields of the molecules that can account for differences in biological activity values. A highly predictive model was attained which supported the results from the qualitative and conventional quantitative structure-activity relationship analyses. These modeling techniques represent the evolutionary process by which structure-activity methods were employed to aid in the development of novel more potent inhibitors of astrocytic chloride transport.

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Authors and Affiliations

  1. Laboratory for Molecular Modeling, Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, 27599-7360

    Chris L. Waller, Steven D. Wyrick, W. Evans Kemp & Hee Moon Park

  2. Department of Pharmacal Sciences, School of Pharmacy, Auburn University, Auburn, Alabama, 36849

    Forrest T. Smith

Authors
  1. Chris L. Waller
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  2. Steven D. Wyrick
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  3. W. Evans Kemp
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  4. Hee Moon Park
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  5. Forrest T. Smith
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Waller, C.L., Wyrick, S.D., Kemp, W.E. et al. Conformational Analysis, Molecular Modeling, and Quantitative Structure–Activity Relationship Studies of Agents for the Inhibition of Astrocytic Chloride Transport. Pharm Res 11, 47–53 (1994). https://doi.org/10.1023/A:1018937425823

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