Neurosteroid analogues: structure-activity studies of benz[e]indene modulators of GABAA receptor function. 1. The effect of 6-methyl substitution on the electrophysiological activity of 7-substituted benz[e]indene-3-carbonitriles.
The effect of 6-methyl substitution of the ability of 7-(2-hydroxyethyl)benz[e]indene-3-carbonitriles to potentiate GABA-mediated chloride current and to directly gate a chloride current in the absence of GABA in cultured rat hippocampal neurons was investigated. Structurally analogous steroid 17-carbonitriles that either contained or did not contain a 19-methyl group were also investigated. Compounds were evaluated at 1 microM for their ability to potentiate GABA-mediated currents and at 10 microM for current activation in the absence of GABA. The benz[e]indene 3(R)-carbonitriles and analogous steroid 17 alpha-carbonitriles had no effects in either assay. The benz[e]indene-3(S)-carbonitriles and analogous steroid 17 alpha-carbonitriles were active in both assays. Relative to the 6-unsubstituted benz[e]indene 3(S)-carbonitrile, the following effects of 6-methyl substituents were observed: a 6(a)-methyl group increased both activities; a 6(e)-methyl group decreased both activities; and 6,6-dimethyl substituents had opposing effects so that both activities remained similar to those of the 6-unsubstituted compound. The activities of the steroid 17 beta-carbonitriles were not affected significantly by the presence or absence of a 19-methyl group. A conformational analysis using molecular modeling methods was also performed for the benz[e]indene 3S-carbonitriles and the steroid 17 beta-carbonitriles. The ability of the different 6-methyl substituents to differentially effect the conformations of the flexible benz[e]indenes and the inability of the steroid 19-methyl group to alter the conformations of the rigid steroid 17 beta-carbonitriles are suggested to explain the results.
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Department of Molecular Biology, Washington University School of Medicine, St. Louis, Missouri 63110.
Zorumski
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Covey
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D000732:Androstanols / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology; D003198:Computer Simulation; D004594:Electrophysiology; D004962:Estranes / Q000138:chemical synthesis / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000732:Androstanols; D018118:Chloride Channels; D004962:Estranes; D009570:Nitriles; D018079:Receptors, GABA; C084683:3-hydroxy-5-estrane-17-carbonitrile; C084682:3-hydroxy-5-androstane-17-carbonitrile; D005680:gamma-Aminobutyric Acid