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J Med Chem
2014 Jan 09;571:171-90. doi: 10.1021/jm401577c.
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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.
Qian M
,
Krishnan K
,
Kudova E
,
Li P
,
Manion BD
,
Taylor A
,
Elias G
,
Akk G
,
Evers AS
,
Zorumski CF
,
Mennerick S
,
Covey DF
.
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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.
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24328079
???displayArticle.pmcLink???PMC3951241 ???displayArticle.link???J Med Chem ???displayArticle.grants???[+]
Akk,
Neurosteroid access to the GABAA receptor.
2005, Pubmed
Akk,
Neurosteroid access to the GABAA receptor.
2005,
Pubmed
Akk,
Mutations of the GABA-A receptor alpha1 subunit M1 domain reveal unexpected complexity for modulation by neuroactive steroids.
2008,
Pubmed
Akk,
Neuroactive steroids have multiple actions to potentiate GABAA receptors.
2004,
Pubmed
Akk,
Kinetic and structural determinants for GABA-A receptor potentiation by neuroactive steroids.
2010,
Pubmed
Bandyopadhyaya,
Neurosteroid analogues. 15. A comparative study of the anesthetic and GABAergic actions of alphaxalone, Δ16-alphaxalone and their corresponding 17-carbonitrile analogues.
2010,
Pubmed
Belelli,
Neurosteroids: endogenous regulators of the GABA(A) receptor.
2005,
Pubmed
Biellmann,
Enantiomeric steroids: synthesis, physical, and biological properties.
2003,
Pubmed
Bracamontes,
A neurosteroid potentiation site can be moved among GABAA receptor subunits.
2012,
Pubmed
Brinton,
Neurosteroids as regenerative agents in the brain: therapeutic implications.
2013,
Pubmed
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
Evers,
A synthetic 18-norsteroid distinguishes between two neuroactive steroid binding sites on GABAA receptors.
2010,
Pubmed
,
Xenbase
Green,
The nonfeminizing enantiomer of 17beta-estradiol exerts protective effects in neuronal cultures and a rat model of cerebral ischemia.
2001,
Pubmed
Han,
Neurosteroid analogues. 4. The effect of methyl substitution at the C-5 and C-10 positions of neurosteroids on electrophysiological activity at GABAA receptors.
1996,
Pubmed
Hawkinson,
Correlation of neuroactive steroid modulation of [35S]t-butylbicyclophosphorothionate and [3H]flunitrazepam binding and gamma-aminobutyric acidA receptor function.
1994,
Pubmed
,
Xenbase
Hosie,
Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites.
2006,
Pubmed
Hu,
Neurosteroid analogues: structure-activity studies of benz[e]indene modulators of GABAA receptor function. 1. The effect of 6-methyl substitution on the electrophysiological activity of 7-substituted benz[e]indene-3-carbonitriles.
1993,
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
Kamijo,
CCl3CN: a crucial promoter of mCPBA-mediated direct ether oxidation.
2010,
Pubmed
Katona,
Synthesis, characterization, and receptor interaction profiles of enantiomeric bile acids.
2007,
Pubmed
Katona,
Neurosteroid analogues. 12. Potent enhancement of GABA-mediated chloride currents at GABAA receptors by ent-androgens.
2008,
Pubmed
Kontonassios,
A-nor steroids. 1. The stereochemistry of a 2-carbomethoxy-A-nor-cholestan-3-one obtained via the Dieckmann condensation.
1982,
Pubmed
Krishnan,
Neurosteroid analogues. 17. Inverted binding orientations of androsterone enantiomers at the steroid potentiation site on γ-aminobutyric acid type A receptors.
2012,
Pubmed
,
Xenbase
Li,
Natural and enantiomeric etiocholanolone interact with distinct sites on the rat alpha1beta2gamma2L GABAA receptor.
2007,
Pubmed
Li,
Dual potentiating and inhibitory actions of a benz[e]indene neurosteroid analog on recombinant alpha1beta2gamma2 GABAA receptors.
2006,
Pubmed
Nace,
Nor steroids. X. Synthesis of A-nor steroids via the Dieckmann condensation.
1973,
Pubmed
Nace,
Nor steroids. IX. Synthesis of A-norandrostanes via the Dieckmann cyclization.
1971,
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
Reddy,
Neurosteroids: endogenous role in the human brain and therapeutic potentials.
2010,
Pubmed
Scaglione,
Neurosteroid analogues. 14. Alternative ring system scaffolds: GABA modulatory and anesthetic actions of cyclopenta[b]phenanthrenes and cyclopenta[b]anthracenes.
2008,
Pubmed
,
Xenbase
Sneitz,
Glucuronidation of the steroid enantiomers ent-17β-estradiol, ent-androsterone and ent-etiocholanolone by the human UDP-glucuronosyltransferases.
2011,
Pubmed
Stastna,
The use of symmetry in enantioselective synthesis: four pairs of chrysene enantiomers prepared from 19-nortestosterone.
2011,
Pubmed
Stastna,
Neurosteroid analogues. 16. A new explanation for the lack of anesthetic effects of δ(16)-alphaxalone and identification of a δ(17(20)) analogue with potent anesthetic activity.
2011,
Pubmed
,
Xenbase
Steinbach,
Modulation of GABA(A) receptor channel gating by pentobarbital.
2001,
Pubmed
Turner,
Steroid anesthetics and naturally occurring analogs modulate the gamma-aminobutyric acid receptor complex at a site distinct from barbiturates.
1989,
Pubmed
VanLandingham,
The enantiomer of progesterone acts as a molecular neuroprotectant after traumatic brain injury.
2006,
Pubmed
Veleiro,
Structure-activity relationships of neuroactive steroids acting on the GABAA receptor.
2009,
Pubmed
Wang,
Neurosteroid Analogues. 13. Synthetic methods for the preparation of 2beta-hydroxygonane derivatives as structural mimics of ent-3alpha-hydroxysteroid modulators of GABA(A) receptors.
2007,
Pubmed
Wittmer,
Enantioselectivity of steroid-induced gamma-aminobutyric acidA receptor modulation and anesthesia.
1996,
Pubmed
,
Xenbase
Zorumski,
Neurosteroids, stress and depression: potential therapeutic opportunities.
2013,
Pubmed
Zorumski,
Neurosteroids as therapeutic leads in psychiatry.
2013,
Pubmed
da Silva,
X-ray and deuterium labeling studies on the abnormal ring cleavages of a 5 beta-epoxide precursor of formestane.
2002,
Pubmed
