Neurosteroid analogues. 17. Inverted binding orientations of androsterone enantiomers at the steroid potentiation site on γ-aminobutyric acid type A receptors

Kathiresan Krishnan, Brad D. Manion, Amanda Taylor, John Bracamontes, Joseph H. Steinbach, David E. Reichert, Alex S. Evers, Charles F. Zorumski, Steven Mennerick, Douglas F. Covey

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17 Scopus citations

Abstract

The enantiomer pair androsterone and ent-androsterone are positive allosteric modulators of γ-aminobutyric acid (GABA) type A receptors. Each enantiomer was shown to bind at the same receptor site. Binding orientations of the enantiomers at this site were deduced using enantiomer pairs containing OBn substituents at either C-7 or C-11. 11β-OBn-substituted steroids and 7α-OBn-substituted ent-steroids potently displace [ 35S]-tert- butylbicyclophosphorothionate, augment GABA currents, and anesthetize tadpoles. In contrast, 7β-OBn-substituted steroids and 11α-OBn-substituted ent-steroids have diminished actions. The results suggest that the binding orientations of the active analogues are inverted relative to each other with the 7α- and 11β-substituents similarly located on the edges of the molecules not in contact with the receptor surface. Analogue potentiation of the GABA current was abrogated by an α 1 subunit Q241L mutation, indicating that the active analogues act at the same sites in α 1β 2γ 2L receptors previously associated with positive neurosteroid modulation.

Original languageEnglish
Pages (from-to)1334-1345
Number of pages12
JournalJournal of Medicinal Chemistry
Volume55
Issue number3
DOIs
StatePublished - Feb 9 2012

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