title: Conformational analysis, molecular modeling, and quantitative structure-activity relationship studies of agents for the inhibition of astrocytic chloride transport.
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.
authors.affiliation: Laboratory for Molecular Modeling, Division of Medicinal Chemistry, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360.
authors.forename: C L
authors.initials: CL
authors.lastname: Waller
authors.forename: S D
authors.initials: SD
authors.lastname: Wyrick
authors.forename: W E
authors.initials: WE
authors.lastname: Kemp
authors.forename: H M
authors.initials: HM
authors.lastname: Park
authors.forename: F T
authors.initials: FT
authors.lastname: Smith
mesh_terms: D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism*; D003864:Depression, Chemical; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D054833:Isoindoles; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D018118:Chloride Channels; D007211:Indoles; D054833:Isoindoles; C014727:1-oxoisoindole