Partial agonist/antagonist properties of androstenedione and 4-androsten-3β,17β-diol

Chen, F.; Knecht, Kristin; Leu, Chih‐Tai; Rutledge, Su Jane; Scafonas, Angela; Gambone, Carlo J.; Vogel, Robert L.; Zhang, H.; Kasparcova, Viera; Bai, Chang; Harada, Satoru; Schmidt, Azriel; Reszka, Alfred A.; Freedman, Leonard P.

doi:10.1016/j.jsbmb.2004.04.009

Cited by 47 publications

(36 citation statements)

References 39 publications

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“…3 H]methyltrienolone (R1881, a potent AR agonist) were as previously described (28). TAMAR assays (transactivation modulation of AR) in 96-well plates used transient transfection of a modified mouse mammary tumor virus (MMTV) long terminal repeat promoter upstream of luciferase (MMTV-LUC).…”

Section: Methodsmentioning

confidence: 99%

“…Chemistry design targeted the generation of compounds that had high affinity binding to AR natively expressed in human MDA-MB-453 breast cancer cells (20,28). Compounds that exhibited apparent binding affinity Ͻ300 nM with little or no displacement of radioligands from related steroid hormone receptors (estrogen receptor ␣, progesterone receptor, or glucocorticoid receptor at 2 M) were tested in the TAMAR assay for their ability to stimulate transcription from the transiently transfected modified MMTV reporter gene (20,28). This assay was chosen because in pilot experiments, TAMAR activities accurately represented the levels of agonism or antagonism of known AR ligands that matched their activities in animal studies or the clinic.…”

Section: Ar Ligands Exhibit Diverse Levels Of Agonism In Threementioning

confidence: 99%

“…Likewise, the compounds were subjected to the TRAF2 assay for measuring the ability of ligands to stimulate the recruitment . Ligand displacement assays with native AR is endogenously expressed in MDA-MB-453 cells as described (28). e, shown is the correlation between Emax values for compounds in TAMAR assay and the activities in VIRCON assay at 300 nM.…”

Section: Ar Ligands Exhibit Diverse Levels Of Agonism In Threementioning

confidence: 99%

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Discovery of the Selective Androgen Receptor Modulator MK-0773 Using a Rational Development Strategy Based on Differential Transcriptional Requirements for Androgenic Anabolism Versus Reproductive Physiology

Schmidt

Kimmel

Bai

et al. 2010

Journal of Biological Chemistry

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Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40 -80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.

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Section: Methodsmentioning

confidence: 99%

Section: Ar Ligands Exhibit Diverse Levels Of Agonism In Threementioning

confidence: 99%

Section: Ar Ligands Exhibit Diverse Levels Of Agonism In Threementioning

confidence: 99%

See 1 more Smart Citation

Discovery of the Selective Androgen Receptor Modulator MK-0773 Using a Rational Development Strategy Based on Differential Transcriptional Requirements for Androgenic Anabolism Versus Reproductive Physiology

Schmidt

Kimmel

Bai

et al. 2010

Journal of Biological Chemistry

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“…5a-DHT is the endpoint of the androgen synthesis pathway and cannot be converted to T or oestrogens and therefore can act only via the androgen receptor. A 4 and T, in contrast, in addition of being ligands of the androgen receptor (Chen et al 2004;Jasuja et al 2005;Sonneveld et al 2005Sonneveld et al , 2006, can be converted to oestrogens (Payne & Hales 2004). Therefore, they can potentially act through an oestrogen receptor pathway.…”

Section: Precocial Speciesmentioning

confidence: 99%

“…Even when acting through the androgen receptor pathway, the three androgens have different affinities for the androgen receptor (5a-DHTOT[A 4 ). The androgen receptor's affinity for A 4 is low (0.1% of 5a-DHT; Holterhus et al 2002;Chen et al 2004;Jasuja et al 2005) and A 4 has a relatively low biological activity. For example, the relative agonistic activity of A 4 in cell-line based in vivo assays is 5.7% of 5a-DHT, while that of T is 14.6% of 5a-DHT (Sonneveld et al 2005(Sonneveld et al , 2006.…”

Section: Precocial Speciesmentioning

confidence: 99%

Hormone-mediated maternal effects in birds:mechanismsmatter but what do we know of them?

Groothuis

Schwabl

2007

Phil. Trans. R. Soc. B

409

426

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Over the past decade, birds have proven to be excellent models to study hormone-mediated maternal effects in an evolutionary framework. Almost all these studies focus on the function of maternal steroid hormones for offspring development, but lack of knowledge about the underlying mechanisms hampers further progress. We discuss several hypotheses concerning these mechanisms, point out their relevance for ecological and evolutionary interpretations, and review the relevant data. We first examine whether maternal hormones can accumulate in the egg independently of changes in hormone concentrations in the maternal circulation. This is important for Darwinian selection and female physiological trade-offs, and possible mechanisms for hormone accumulation in the egg, which may differ among hormones, are reviewed. Although independent regulation of plasma and yolk concentrations of hormones is conceivable, the data are as yet inconclusive for ovarian hormones. Next, we discuss embryonic utilization of maternal steroids, since enzyme and receptor systems in the embryo may have coevolved with maternal effect mechanisms in the mother. We consider doseresponse relationships and action pathways of androgens and argue that these considerations may help to explain the apparent lack of interference of maternal steroids with sexual differentiation. Finally, we discuss mechanisms underlying the pleiotropic actions of maternal steroids, since linked effects may influence the coevolution of parent and offspring traits, owing to their role in the mediation of physiological trade-offs. Possible mechanisms here are interactions with other hormonal systems in the embryo. We urge endocrinologists to embark on suggested mechanistic studies and behavioural ecologists to adjust their interpretations to accommodate the current knowledge of mechanisms.

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Nuclear Receptors and NR ‐coregulators: Mechanism of Action and Cell Signaling

Bhan

Mandal

2017

Gene Regulation, Epigenetics and Hormone Signaling

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Partial agonist/antagonist properties of androstenedione and 4-androsten-3β,17β-diol

Cited by 47 publications

References 39 publications

Discovery of the Selective Androgen Receptor Modulator MK-0773 Using a Rational Development Strategy Based on Differential Transcriptional Requirements for Androgenic Anabolism Versus Reproductive Physiology

Discovery of the Selective Androgen Receptor Modulator MK-0773 Using a Rational Development Strategy Based on Differential Transcriptional Requirements for Androgenic Anabolism Versus Reproductive Physiology

Hormone-mediated maternal effects in birds:mechanismsmatter but what do we know of them?

Nuclear Receptors and NR ‐coregulators: Mechanism of Action and Cell Signaling

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