Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Med Chem
2012 Feb 09;553:1334-45. doi: 10.1021/jm2014925.
Show Gene links
Show Anatomy links
Neurosteroid analogues. 17. Inverted binding orientations of androsterone enantiomers at the steroid potentiation site on γ-aminobutyric acid type A receptors.
Krishnan K
,
Manion BD
,
Taylor A
,
Bracamontes J
,
Steinbach JH
,
Reichert DE
,
Evers AS
,
Zorumski CF
,
Mennerick S
,
Covey DF
.
???displayArticle.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 [(35)S]-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(1)β(2)γ(2L) receptors previously associated with positive neurosteroid modulation.
???displayArticle.pubmedLink???
22191644
???displayArticle.pmcLink???PMC3276733 ???displayArticle.link???J Med Chem ???displayArticle.grants???[+]
Akk,
Kinetic and structural determinants for GABA-A receptor potentiation by neuroactive steroids.
2010, Pubmed
Akk,
Kinetic and structural determinants for GABA-A receptor potentiation by neuroactive steroids.
2010,
Pubmed
Akk,
Mutations of the GABA-A receptor alpha1 subunit M1 domain reveal unexpected complexity for modulation by neuroactive steroids.
2008,
Pubmed
Belelli,
Neurosteroids: endogenous regulators of the GABA(A) receptor.
2005,
Pubmed
Bracamontes,
Steroid interaction with a single potentiating site is sufficient to modulate GABA-A receptor function.
2009,
Pubmed
,
Xenbase
Chisari,
The influence of neuroactive steroid lipophilicity on GABAA receptor modulation: evidence for a low-affinity interaction.
2009,
Pubmed
,
Xenbase
Chisari,
The sticky issue of neurosteroids and GABA(A) receptors.
2010,
Pubmed
Covey,
Enantioselectivity of pregnanolone-induced gamma-aminobutyric acid(A) receptor modulation and anesthesia.
2000,
Pubmed
Hamilton,
Interaction of steroids with the GABA(A) receptor.
2002,
Pubmed
Hawkins,
Comparison of shape-matching and docking as virtual screening tools.
2007,
Pubmed
Hosie,
Conserved site for neurosteroid modulation of GABA A receptors.
2009,
Pubmed
Hosie,
Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites.
2006,
Pubmed
Jiang,
Neurosteroid analogues. 9. Conformationally constrained pregnanes: structure-activity studies of 13,24-cyclo-18,21-dinorcholane analogues of the GABA modulatory and anesthetic steroids (3alpha,5alpha)- and (3alpha,5beta)-3-hydroxypregnan-20-one.
2003,
Pubmed
,
Xenbase
Katona,
Enantiomeric deoxycholic acid: total synthesis, characterization, and preliminary toxicity toward colon cancer cell lines.
2007,
Pubmed
Katona,
Neurosteroid analogues. 12. Potent enhancement of GABA-mediated chloride currents at GABAA receptors by ent-androgens.
2008,
Pubmed
Lambert,
Neurosteroids: endogenous allosteric modulators of GABA(A) receptors.
2009,
Pubmed
Li,
Natural and enantiomeric etiocholanolone interact with distinct sites on the rat alpha1beta2gamma2L GABAA receptor.
2007,
Pubmed
Nilsson,
Neurosteroid analogues. 6. The synthesis and GABAA receptor pharmacology of enantiomers of dehydroepiandrosterone sulfate, pregnenolone sulfate, and (3alpha,5beta)-3-hydroxypregnan-20-one sulfate.
1998,
Pubmed
Phillipps,
Structure-activity relationships in steroidal anaesthetics.
1975,
Pubmed
Reddy,
Neurosteroids: endogenous role in the human brain and therapeutic potentials.
2010,
Pubmed
Shen,
Efficient synthesis of IPL576,092: a novel anti-asthma agent.
2002,
Pubmed
Shu,
Cyclodextrins sequester neuroactive steroids and differentiate mechanisms that rate limit steroid actions.
2007,
Pubmed
,
Xenbase
Veleiro,
Structure-activity relationships of neuroactive steroids acting on the GABAA receptor.
2009,
Pubmed
Wang,
3beta -hydroxypregnane steroids are pregnenolone sulfate-like GABA(A) receptor antagonists.
2002,
Pubmed
,
Xenbase
Wittmer,
Enantioselectivity of steroid-induced gamma-aminobutyric acidA receptor modulation and anesthesia.
1996,
Pubmed
,
Xenbase
Zeng,
Neurosteroid analogues. 10. The effect of methyl group substitution at the C-6 and C-7 positions on the GABA modulatory and anesthetic actions of (3alpha,5alpha)- and (3alpha,5beta)-3-hydroxypregnan-20-one.
2005,
Pubmed
,
Xenbase
Zorumski,
Potential clinical uses of neuroactive steroids.
2000,
Pubmed
