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PubMed · 8140055

Conformational analysis, molecular modeling, and quantitative structure-activity relationship studies of agents for the inhibition of astrocytic chloride transport.

C L Waller·S D Wyrick·W E Kemp·H M Park·F T Smith
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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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AstrocytesChloride ChannelsDepression, ChemicalIndolesIsoindolesModels, MolecularMolecular ConformationStructure-Activity RelationshipJournal Article

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C L Waller, S D Wyrick, W E Kemp, H M Park, F T Smith. 1994. Conformational analysis, molecular modeling, and quantitative structure-activity relationship studies of agents for the inhibition of astrocytic chloride transport.. https://doi.org/10.1023/a%3A1018937425823

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