Neurosteroid Analogues. 8. Structure−Activity Studies of <i>N</i>-Acylated 17a-Aza-D-homosteroid Analogues of the Anesthetic Steroids (3α,5α)- and (3α,5β)-3-Hydroxypregnan-20-one

Covey, Douglas F.; Han, Mei; Kumar, Aman; Cruz, Maria Antonette M. de la; Meadows, Eric S.; Hu, Yuefei; Tonnies, Alicia; Nathan, Devi; Coleman, Melissa L.; Benz, Ann; Evers, Alex S.; Zorumski, § Charles F.; Mennerick, Steven

doi:10.1021/jm0002477

Cited by 25 publications

(21 citation statements)

References 13 publications

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“…Similar results were evident in cells treated with the PI3K inhibitor wortmannin, the Akt-inhibiting PI analog 1L-6-Hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate (Covey et al 2000), or geldanamycin, an HSP-90 inhibitor chemically distinct from radicicol, as Bcl-x L -and Pim-2-expressing cells were minimally affected and the drugs abrogated the protective effect of mAkt (data not shown). Thus, Pim-2 can maintain survival independently of the activities of PI3K, HSP-90, and Akt.…”

Section: Pim-2 Is An Apoptotic Inhibitor Genes and Development 1847supporting

confidence: 69%

The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor

Fox¹,

Hammerman²,

Cinalli³

et al. 2003

Genes Dev.

302

341

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Growth factor withdrawal results in the termination of factor-dependent transcription. One transcript that declines rapidly following growth factor deprivation of hematopoietic cells is the serine/threonine kinase pim-2. When constitutively expressed, Pim-2 conferred long-term resistance to a variety of apoptotic stimuli including growth factor withdrawal and endogenous levels of Pim-2 contributed to growth factor-mediated apoptotic resistance. Pim-2 expression maintained cell size and mitochondrial potential independently of the PI3K/Akt/TOR pathway. Pim-2-dependent maintenance of cell size and survival correlated with its ability to maintain rapamycin-resistant phosphorylation of the translational repressor 4E-BP1 and phosphorylation of the BH3 protein BAD. These results establish Pim-2 as a direct link between growth factor-induced transcription and a novel, kinase-dependent pathway that promotes cell-autonomous survival.

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Section: Pim-2 Is An Apoptotic Inhibitor Genes and Development 1847supporting

confidence: 69%

The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor

Fox¹,

Hammerman²,

Cinalli³

et al. 2003

Genes Dev.

302

341

View full text Add to dashboard Cite

show abstract

“…Steroid enantiomers also offer interesting prospects for the treatment of lesions and diseases of the nervous system. Enantiomers are symmetrical, nonsuperimposable structures (mirror images) of molecules, with identical physical properties (except for the different rotation of polarized light) [154]. The synthetic ())enantiomer of pregnenolone sulfate (PREGS) was found to be 10 times more potent in activating memory functions than natural (+)PREGS.…”

Section: Discussionmentioning

confidence: 99%

Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination

Schumacher

Guennoun

Robert

et al. 2004

Growth Hormone & IGF Research

203

134

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“…In line with the above studies, Covey and coworkers prepared and evaluated a series of 13,24-cyclo-18,21-dinorcholanes containing a ketone or a conjugated ketone group at C-20, C-22, C-23 or C-24 (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) [28]. These ana- logues with conformationally constrained side chains were used to gain new information concerning the optimal location(s) for a hydrogen bond accepting group on the D-ring.…”

Section: Modifications At the D Ring And The Side Chainmentioning

confidence: 97%

“…coworkers prepared a series of 17a-aza-Dhomosteroids (60-67) and evaluated their activity in binding experiments using [ 35 S]TBPS displacement and in electrophysiological experiments measuring the effects on the responses of rat 1 2 2 GABA A receptors expressed in Xenopus oocytes[31]. Except for compound 62, there was a substantial decrease in [ 35 S]TBPS displacement activity compared to the corresponding reference compounds 1-3, the deleterious effect being much stronger in the 5 series (up to two orders of magnitude).While the substitution of the N-acetyl group in 60 and 61 by an -hydroxyacetyl…”

mentioning

confidence: 99%

Structure-Activity Relationships of Neuroactive Steroids Acting on the GABAA Receptor

Veleiro

Burton²

2009

CMC

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The term "neuroactive steroid" (NAS) refers to steroids which, independent of their origin, are capable of modifying neural activities. These steroids positively or negatively modulate the function of members of the ligand-gated ion channel superfamily. Those with positive allosteric actions on the gamma-amino butyric acid type A receptor (GABAA receptor) have been shown to be potent anticonvulsants, anxiolytics, and antistress agents and to possess sedative, hypnotic, and anesthetic activities. New types of neuroactive steroids have been widely sought and structural modifications of the naturally occurring metabolites allopregnanolone, pregnanolone and allotetrahydrodeoxycorticosterone, have been examined in the light of the vast family of GABA receptor subtypes within the brain. Here we review the structure-activity relationship (SAR) of neuroactive steroid analogues obtained by modification of the steroid nucleus, including substitutions at the A, B, C, and D rings and the side chain, with emphasis on the different pharmacophores proposed.

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Neurosteroid Analogues. 8. Structure−Activity Studies of N-Acylated 17a-Aza-D-homosteroid Analogues of the Anesthetic Steroids (3α,5α)- and (3α,5β)-3-Hydroxypregnan-20-one

Cited by 25 publications

References 13 publications

The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor

The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor

Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination

Structure-Activity Relationships of Neuroactive Steroids Acting on the GABAA Receptor

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