title: Neurosteroid analogues. 18. Structure-activity studies of ent-steroid potentiators of γ-aminobutyric acid type A receptors and comparison of their activities with those of alphaxalone and allopregnanolone.
abstract: A model of the alignment of neurosteroids and ent-neurosteroids at the same binding site on γ-aminobutyric acid type A (GABAA) receptors was evaluated for its ability to identify the structural features in ent-neurosteroids that enhance their activity as positive allosteric modulators of this receptor. Structural features that were identified included: (1) a ketone group at position C-16, (2) an axial 4α-OMe group, and (3) a C-18 methyl group. Two ent-steroids were identified that were more potent than the anesthetic steroid alphaxalone in their threshold for and duration of loss of the righting reflex in mice. In tadpoles, loss of righting reflex for these two ent-steroids occurs with EC50 values similar to those found for allopregnanolone. The results indicate that ent-steroids have considerable potential to be developed as anesthetic agents and as drugs to treat brain disorders that are ameliorated by positive allosteric modulators of GABAA receptor function.
authors: Departments of Developmental Biology, ‡Anesthesiology, §Psychiatry, and ⊥Anatomy and Neurobiology, Washington University in St. Louis School of Medicine , St. Louis, Missouri, 63110, United States.
authors: Mingxing
authors: M
authors: Qian
authors: Kathiresan
authors: K
authors: Krishnan
authors: Eva
authors: E
authors: Kudova
authors: Ping
authors: P
authors: Li
authors: Brad D
authors: BD
authors: Manion
authors: Amanda
authors: A
authors: Taylor
authors: George
authors: G
authors: Elias
authors: Gustav
authors: G
authors: Akk
authors: Alex S
authors: AS
authors: Evers
authors: Charles F
authors: CF
authors: Zorumski
authors: Steven
authors: S
authors: Mennerick
authors: Douglas F
authors: DF
authors: Covey
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D018757:GABA Modulators / Q000138:chemical synthesis* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D018377:Neurotransmitter Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D011277:Pregnanediones / Q000494:pharmacology*; D011280:Pregnanolone / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018757:GABA Modulators; D018377:Neurotransmitter Agents; D011277:Pregnanediones; D011963:Receptors, GABA-A; C037476:tert-butylbicyclophosphorothionate; C006477:alphaxalone; D011280:Pregnanolone