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

Mingcheng Han, Yuefei Hu, Charles F. Zorumski, Douglas F. Covey

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Abstract

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 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 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.

Original languageEnglish
Pages (from-to)4548-4556
Number of pages9
JournalJournal of Medicinal Chemistry
Volume38
Issue number22
DOIs
StatePublished - Oct 1 1995

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