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

ABSTRACT: The enantiomer pair androsterone and ent-androsterone are positive allosteric modulators of ?-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. 11?-OBn-substituted steroids and 7?-OBn-substituted ent-steroids potently displace [(35)S]-tert-butylbicyclophosphorothionate, augment GABA currents, and anesthetize tadpoles. In contrast, 7?-OBn-substituted steroids and 11?-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 7?- and 11?-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 ?(1) subunit Q241L mutation, indicating that the active analogues act at the same sites in ?(1)?(2)?(2L) receptors previously associated with positive neurosteroid modulation.

SUBMITTER: Krishnan K 

PROVIDER: S-EPMC3276733 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature