Although the structural features of binding sites for neuroactive steroids on γ-aminobutryic acid type A (GABAA) receptors are still largely unknown, structure-activity studies have established a pharmacophore for potent enhancement of GABAA receptor function by neuroactive steroids. This pharmacophore emphasizes the importance of the position and stereochemistry of hydrogen-bonding groups on the steroid. However, the importance of the steroid ring system in mediating hydrophobic interactions with the GABAA receptor is unclear. We have taken the cyclopenta[b]phenanthrene (tetracyclic compounds with a nonlinear ring system different from that of steroids) and cyclopenta[b]anthracene (tetracyclic molecules with a linear 6-6-6-5 carbocyclic ring system) ring systems and properly substituted them to satisfy the pharmacophore requirements of the critical hydrogen-bond donor and acceptor groups found in neuroactive steroids. We have found these cyclopenta[b]phenanthrene and cyclopenta[b]anthracene analogues to have potent activity at the GABAA receptor, rivaling that of the most potent steroid modulators. Single-channel analysis of electrophysiological data indicates that similarly substituted analogues in the different ring systems affect the kinetic components of macroscopic currents in different ways. Mutations to the hydrogen bonding amino acids at the putative steroid binding site (α1Q241L mutation and α1N407A/Y410F double mutation) produce similar effects on macroscopic current amplitude by the different ring system analogues suggesting that the different kinetic effects are explained by the precise interactions of each analogue with the same binding site(s).

Original languageEnglish
Pages (from-to)1309-1318
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number5
StatePublished - Mar 13 2008


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