NEUROSTEROID ANALOGS - STRUCTURE-ACTIVITY STUDIES OF BENZ[E]INDENE MODULATORS OF GABA(A) 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 on the ability of 7-(2-hydroxyethy l)benz[e]indene-3-carbonitriles to potentiate GABA-mediated chloride c urrent and to directly gate a chloride current in the absence of GABA in cultured rat hippocampal neurons was investigated. Structurally ana logous steroid 17-carbonitriles that either contained or did not conta in a 19-methyl group were also investigated. Compounds were evaluated at 1 mu M for their ability to potentiate GABA-mediated currents and a t 10 mu M for current activation in the absence of GABA. The benz[e]in dene 3(R)-carbonitriles and analogous steroid 17 alpha-carbonitriles h ad no effects in either assay. The benz[e]indene-3(S)-carbonitriles an d analogous steroid 17 beta-carbonitriles were active in both assays. Relative to the g-unsubstituted benz[e]indene 3(S)-carbonitrile, the f ollowing effects of 6-methyl substituents were observed: a 6(a)-methyl group increased both activities; a 6(e)-methyl group decreased both a ctivities; and 6,6-dimethyl substitutents had opposing effects so that both activites remained similar to those of the 6-unsubstituted compo und. The activities of the steroid 17 beta-carbonitriles were not affe cted significantly by the presence or absence of a 19-methyl group. A conformational analysis using molecular modeling methods was also perf ormed for the benz[e]indene 3S-carbonitriles and the steroid 17 beta-c arbonitriles. The ability of the different 6-methyl substituents to di fferentially effect the conformations of the flexible benz[e]indenes a nd the inability of the steroid 19-methyl group to alter the conformat ions of the rigid steroid 17 beta-carbonitriles are suggested to expla in the results.