A series of optical, structural and isomeric analogs of estradiol: A comparative study of the biological activity and affinity to cytosol receptor of rabbit uterus

Chernayaev, G.A.; Barkova, T.I.; Egorova, V. V.; Sorokina, I B; Ananchenko, S. N.; Mataradze, G. D.; Sokolova, N. A.; Rozen, V. B.

doi:10.1016/0022-4731(75)90201-0

Cited by 38 publications

(14 citation statements)

References 21 publications

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“…For example, the complete enantiomer of 17β-E2 (ent-17β-E2) has identical physiochemical properties as 17β-E2 except for interactions with other stereospecific molecules such as ERs. Ent-17β-E2 is reported to interact only weakly with uterine-derived ERs [60, 61] and lacks estrogenic effects on reproductive tissues in rodents [62, 63]. In fact, some reports indicate that ent-17β-E2 exerts slight anti-uterotrophic activity and can antagonize the uterotrophic effects of 17β-E2 [63, 64].…”

Section: Estrogens and Neuroproptectionmentioning

confidence: 99%

Mitochondrial mechanisms of estrogen neuroprotection

Simpkins

Yang

et al. 2010

Biochimica et Biophysica Acta (BBA) - General Subjects

148

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Mitochondria have become a primary focus in our search not only for the mechanism(s) of neuronal death but also for neuroprotective drugs and therapies that can delay or prevent Alzheimer's disease and other chronic neurodegenerative conditions. This is because mitochrondria play a central role in regulating viability and death of neurons, and mitochondrial dysfunction has been shown to contribute to neuronal death seen in neurodegenerative diseases. In this article, we review the evidence for the role of mitochondria in cell death and neurodegeneration and provide evidence that estrogens have multiple effects on mitochondria that enhance or preserve mitochondrial function during pathologic circumstances such as excitotoxicity, oxidative stress, and others. As such, estrogens and novel non-hormonal analogs have come to figure prominently in our efforts to protect neurons against both acute brain injury and chronic neurodegeneration. Keywordsestrogens; estradiol; non-feminizing estrogens mitochondria; neuroprotection; estrogen receptors; Alzheimer's disease Mitochondrial and cell death mechanismsMitochondrial oxidative phosphorylation is essential for neurons to meet their high ATP demand, and neuronal viability is imperiled when this ATP production is even transiently diminished. In addition to a bioenergetic crisis, mitochondrial impairment also produces a concomitant increase in production of reactive oxygen species [1]. Mitochondrial failure is the key event in the pathogenic cascade leading to ischemia-induced cell death from both necrosis and apoptosis [1,2]. Under conditions of oxidative stress and excessive cytoplasmic Ca 2+ loading, mitochondria undergo a loss of the impermeability of the inner mitochondrial membrane that completely collapses the mitochondrial membrane potential (ΔΨm), a process called permeability transition. Such irreversible collapse of ΔΨm is accompanied by mitochondrial swelling and release of cytochrome c into the cytoplasm, where it activates certain caspases and induces apoptotic cell death [2,3].Normally, antioxidant defense systems reduce radical-induced damage by scavenging free radicals. However, accelerated mitochondrial radical production can overwhelm these Send correspondence to: James W. Simpkins, Ph.D., Department of Pharmacology & Neuroscience, Room RES-334J, University of North Texas Health Science Center, 3500 Camp Bowie Bvld., Fort Worth, TX 76107, Phone 817-735-0498, jsimpkin@hsc.unt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBiochim Biophys Acta. Author manuscript; availa...

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Section: Estrogens and Neuroproptectionmentioning

confidence: 99%

Mitochondrial mechanisms of estrogen neuroprotection

Simpkins

Yang

et al. 2010

Biochimica et Biophysica Acta (BBA) - General Subjects

148

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“…2a and b), respectively, and that the molecules (particularly DES) are not as flat as their conventional chemical drawings might suggest. The small but significant difference between the oxygen-oxygen distances in these structures cannot be overcome by 9' b) 8 6' 5' molecular flexibility. The fairly rigid fused ring system of estradiol and the central double bond in DES prevent the oxygen from getting more than 0.1 A closer to each other.…”

Section: Estradiol and Diethylstilbestrolmentioning

confidence: 99%

“…Simple compounds such as tetrahya) dronaphthol and p-sec-amyl phenol prevent or compete for the binding of estradiol to its receptor (7). Chernyaev et al (8) have demonstrated that the removal of the 3-hydroxyl substituent significantly decreases receptor binding while retaining some portion of biological activity. Removal of the 17-hydroxyl was shown to decrease binding to a lesser extent than 3-hydroxyl removal but to almost totally abolish biological activity (8).…”

Section: Introductionmentioning

confidence: 99%

Molecular conformation, receptor binding, and hormone action of natural and synthetic estrogens and antiestrogens.

Duax¹,

Griffin²,

Weeks³

et al. 1985

Environ Health Perspect

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The X-ray crystallographic structural determinations of synthetic estrogens and antiestrogens provide reliable information on the global minimum energy conformation of these molecules or a local minimum energy conformation that is within 1 or 2 kcal/mole of the global minimum. In favorable cases, state-ofthe-art molecular mechanics calculations provide quantitative agreement with X-ray results and information on the relative energy ofother local minimum energy conformations not observed crystallographically.Because the conformation of diethylstilbestrol (DES) observed in solvated crystals has an overall conformation and dipole moment more similar to estradiol it is the form more likely to bind to the receptor and produce hormone activity. Either phenol ring of DES can successfully mimic the estradiol A-ring in binding to the receptor. Indenestrol A (INDA) and indenestrol B (INDB) have nearly identical fully extended planar conformations. Either the a or y rings of these compounds may mimic the A ring of estradiol and compete for the estrogen receptor. Although there are eight distinct ways in which molecules of a racemic mixture of INDA or INDB can bind to the receptor, not all of them may be able to elicit a hormonal response. This may account for the reduced biological activity of the compounds despite their successful competition for receptor binding.The minimum energy conformations of Z-pseudodiethylstilbestrol (ZPD) and E-pseudodiethylstilbestrol (EPD) are bent in a fashion similar to that of indanestrol (INDC). These molecules have good binding affinity suggesting that the receptor does not require a flat molecule. Therefore these conformations would appear to be compatible with receptor binding, but only the Z isomer has an energetically allowed extended conformation that accounts for its observed biological activity relative to DES.

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“…Ent-E 2 has been previously reported to have 0.9 -6% of ␤E 2 's relative binding affinity to cytosolic uterine ERs (27,28). Ent-E 2 has been previously reported to have 0.9 -6% of ␤E 2 's relative binding affinity to cytosolic uterine ERs (27,28).…”

Section: Ent-e 2 Is a Weak Er Agonist/antagonistmentioning

confidence: 98%

The Nonfeminizing Enantiomer of 17β-Estradiol Exerts Protective Effects in Neuronal Cultures and a Rat Model of Cerebral Ischemia**This work was supported by NIH Grants AG-10485 (to J.W.S.) and GM- 47969 (to D.F.C.), U.S. Army Grant DAMD-17–99-1–9473 (to J.W.S.), and Apollo Biopharmaceutics, Inc. funding (to J.W.S. and D.F.C.).

et al. 2001

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Estrogens are potent neuroprotective compounds in a variety of animal and cell culture models, and data indicate that estrogen receptor (ER)-mediated gene transcription is not required for some of these effects. To further address the requirement for an ER in estrogen enhancement of neuronal survival, we assessed the enantiomer of 17beta-estradiol (ENT-E(2)), which has identical chemical properties but interacts only weakly with known ERs, for neuroprotective efficacy. ENT-E(2) was both as potent and efficacious as 17beta-estradiol in attenuating oxidative stress-induced death in HT-22 cells, a murine hippocampal cell line. Further, ENT-E(2) completely attenuated H(2)O(2) toxicity in human SK-N-SH neuroblastoma cells at a 10 nM concentration. In a rodent model of focal ischemia, 17beta-estradiol (100 microgram/kg) or ENT-E(2) (100 microgram/kg), injected 2 h before middle cerebral artery occlusion, resulted in a 60 and 61% reduction in lesion volume, respectively. ENT-E(2), at the doses effective in this study, did not stimulate uterine growth or vaginal opening in juvenile female rats when administered daily for 3 days. These data indicate that the neuroprotective effects of estrogens, both in vitro and in vivo, can be disassociated from the peripheral estrogenic actions.

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A series of optical, structural and isomeric analogs of estradiol: A comparative study of the biological activity and affinity to cytosol receptor of rabbit uterus

Cited by 38 publications

References 21 publications

Mitochondrial mechanisms of estrogen neuroprotection

Mitochondrial mechanisms of estrogen neuroprotection

Molecular conformation, receptor binding, and hormone action of natural and synthetic estrogens and antiestrogens.

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