Neurosteroid Analogues; Structure-Activity Studies of Benzindene Modulators of GABAA Receptor Function. 1. The effect of 6-Methyl Substitution on the Electrophysiological Activity of 7-Substituted Benzindene-3-carbonitriles

Article abstract of DOI:10.1021/jm00076a025

The effect of 6-methyl substitution on the ability of 7-(2-hydroxyethyl)benzindene-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 μM for their ability to potentiate GABA-mediated currents and at 10 μM for current activation in the absence of GABA.The benzindene 3(R)-carbonitriles and analogous steroid 17α-carbonitriles had no effects in either assay.The benzindene-3(S)-carbonitriles and analogous steroid 17β-carbonitriles were active in both assays.Relative to the 6-unsubstituted benzindene 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 activites remained similar to those of the 6-unsubstituted compound.The activities of the steroid 17β-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 benzindene 3S-carbonitriles and the steroid 17β-carbonitriles.The ability of the different 6-methyl substituents to differentially effect the conformations of the flexible benzindenes and the inability of the steroid 19-methyl group to alter the conformations of the rigid steroid 17β-carbonitriles are suggested to explain the results.