Neurosteroid analogues. 3. The synthesis and electrophysiological evaluation of benz[e]indene congeners of neuroactive steroids having the 5 beta-configuration.

A series of 7-(2-hydroxyethyl)benz[e]indene analogues of 3 alpha-hydroxy-5 beta-pregnan-20-one (7), a neuroactive steroid known to be a positive allosteric modulator of GABAA receptor function, was prepared. Electrophysiological measurements carried out on cultured rat hippocampal neurons were used to evaluate the modulatory effects of the analogues on GABAA receptor function. Analogues were tested for their ability to potentiate 1 microM GABA-mediated chloride currents and for their ability to directly gate chloride currents at this ligand-gated ion channel. Active analogues typically enhanced GABA-mediated currents at concentrations below those required to directly gate chloride currents. The dose-response relationships for potentiation of 1 microM GABA-mediated chloride currents were studied for [3S-(3 alpha, 3a alpha, 5a beta, 7 beta, 9a alpha, 9b beta)]-1- [dodecahydro-7-(2-hydroxyethyl)-3a-methyl-1H-benz[e]inden-3- yl]ethanone (3), steroid 7, 3 alpha-hydroxy-5 alpha-pregnan-20-one (5), and the analogous 7 alpha-(2-hydroxyethyl)benz[e]indene analogue of steroid 5 (compound 1). Compound 3 was the most active potentiator (EC50 = 0.017 microM) of GABA-mediated current. The direct gating actions of compound 3 were not observed at a concentration of 1 microM, but were observed at a concentration of 10 microM.