Neurosteroid Analogues. 3. The Synthesis and Electrophysiological Evaluation of Benz[e]indene Congeners of Neuroactive Steroids Having the 5β-Configuration

A series of 7-(2-hydroxyethyl)benz[e]indene analogues of 3α-hydroxy-5β-pregnan-20-one (7), a neuroactive steroid known to be a positive allosteric modulator of GABA_A receptor function, was prepared. Electrophysiological measurements carried out on cultured rat hippocampal neurons were used to evaluate the modulatory effects of the analogues on GABA_A receptor function. Analogues were tested for their ability to potentiate 1 μM 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 μM GABA-mediated chloride currents were studied for [3S-(3α,3aα,5aβ,7β,9aα,9bβ)]-1-[dodecahydro-7-(2-hydroxyethyl)-3a-methyl-1H-benz[e]inden-3-yl]ethanone (3), steroid 7, 3α-hydroxy-5α-pregnan-20-one (5), and the analogous 7α-(2-hydroxyethyl)benz[e]indene analogue of steroid 5 (compound 1). Compound 3 was the most active potentiator (EC₅₀ = 0.017 μM) of GABA-mediated current. The direct gating actions of compound 3 were not observed at a concentration of 1 μM, but were observed at a concentration of 10 μM.