Structure–activity relationship (SAR) analysis of a family of steroids acutely controlling steroidogenesis

Midzak, Andrew; Rammouz, Georges; Papadopoulos, Vassilios

doi:10.1016/j.steroids.2012.08.019

Cited by 12 publications

(5 citation statements)

References 35 publications

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“…This has led to the identification and experimental validation of several alternative steroidal CRAC domain ligands (Midzak et al, 2011) able to potently inhibit steroidogenesis in mouse and rat Leydig tumor cell lines. These results indicate that not only is the drug-binding site a pharmacological target for control of steroidogenesis, but that the C-terminal CRAC motif of the protein is as well (Midzak et al, 2011; Midzak et al, 2012). Compounds targeting TSPO’s CRAC motif may thus serve as pharmacological leads for the treatment of diseases of steroidal excess, such as Cushing’s disease in humans and animals (Biller et al, 2008), as well as a variety of endocrine tumors (Freeman, 1986).…”

Section: Pharmacological Targeting Of Tspo For Inhibition Of Steromentioning

confidence: 86%

Translocator protein-mediated pharmacology of cholesterol transport and steroidogenesis

Papadopoulos

Aghazadeh

Fan

et al. 2015

Molecular and Cellular Endocrinology

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108

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Steroidogenesis begins with cholesterol transfer into mitochondria through the transduceosome, a complex composed of cytosolic proteins that include steroidogenesis acute regulatory protein (STAR), 14-3-3 adaptor proteins, and the outer mitochondrial membrane proteins Translocator Protein (TSPO) and Voltage-Dependent Anion Channel (VDAC). TSPO is a drug- and cholesterol- binding protein found at particularly high levels in steroid synthesizing cells. Its aberrant expression has been linked to cancer, neurodegeneration, neuropsychiatric disorders and primary hypogonadism. Brain steroids serve as local regulators of neural development and excitability. Reduced levels of these steroids have been linked to depression, anxiety and neurodegeneration. Reduced serum testosterone is common among subfertile young men and aging men, and is associated with depression, metabolic syndrome and reduced sexual function. Although testosterone-replacement therapy is available, there are undesired side-effects. TSPO drug ligands have been proposed as therapeutic agents to regulate steroid levels in the brain and testis.

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Section: Pharmacological Targeting Of Tspo For Inhibition Of Steromentioning

confidence: 86%

Translocator protein-mediated pharmacology of cholesterol transport and steroidogenesis

Papadopoulos

Aghazadeh

Fan

et al. 2015

Molecular and Cellular Endocrinology

Self Cite

108

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“…5-Androsten-3,17,19-triol (19-Atriol) was synthesized as previously described (39). M-199 was from Gibco BRL (Grand Island, New York).…”

Section: Reagentsmentioning

confidence: 99%

“…Freshly isolated Leydig cells were suspended in M-199 culture media and plated at a density of 3-5 ϫ To determine whether TSPO ligands affected TSPO, Leydig cells were preincubated for 30 minutes with 19-Atriol, a specific inhibitor of the TSPO CRAC domain (39,41), dissolved in dimethylsulfoxide (final concentration in culture medium less than 0.5%), and then further incubated for 2 h with 19-Atriol plus LH, Ro5-4864, or FGIN-1-27. T was measured by RIA after HPLC separation of steroids (42).…”

Section: Effect Of Tspo Drug Ligands On Steroid Production In Vitromentioning

confidence: 99%

Drug Ligand-Induced Activation of Translocator Protein (TSPO) Stimulates Steroid Production by Aged Brown Norway Rat Leydig Cells

et al. 2013

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Translocator protein (TSPO; 18 kDA) is a high-affinity cholesterol-binding protein that is integrally involved in cholesterol transfer from intracellular stores into mitochondria, the rate-determining step in steroid formation. Previous studies have shown that TSPO drug ligands are able to activate steroid production by MA-10 mouse Leydig tumor cells and by mitochondria isolated from steroidogenic cells. We hypothesized herein that the direct, pharmacological activation of TSPO might induce aged Leydig cells, which are characterized by reduced T production, to produce significantly higher levels of T both in vitro and in vivo. To test this, we first examined the in vitro effects of the TSPO selective and structurally distinct drug ligands N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27) and benzodiazepine 4Ј-chlorodiazepam (Ro5-4864) on steroidogenesis by Leydig cells isolated from aged (21-24 months old) and young adult (3-6 months old) Brown Norway rats. The ligands stimulated Leydig cell T production significantly, and equivalently, in cells of both ages, an effect that was significantly inhibited by the specific TSPO inhibitor 17,. Additionally, we examined the in vivo effects of administering FGIN-1-27 to young and aged rats. In both cases, serum T levels increased significantly, consistent with the in vitro results. Indeed, serum T levels in aged rats administered FGIN-1-27 were equivalent to T levels in the serum of control young rats. Taken together, these results indicate that although there are reduced amounts of TSPO in aged Leydig cells, its direct activation is able to increase T production. We suggest that this approach might serve as a therapeutic means to increase steroid levels in vivo in cases of primary hypogonadism. (Endocrinology 154: 2156 -2165, 2013)

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“…2). The reactivity of steroids depends on the functional groups attached to the tetracyclic backbone [40]. When comparing P5 derivatives with modifications Among all the P5 derivatives that we synthesized, compound #43 is the most effective one that promotes microtubule polymerization (Fig.…”

Section: Discussionmentioning

confidence: 99%

A synthetic pregnenolone analog promotes microtubule dynamics and neural development

et al. 2022

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Background Pregnenolone (P5) is a neurosteroid that promotes microtubule polymerization. It also reduces stress and negative symptoms of schizophrenia, promotes memory, as well as recovery from spinal cord injury. P5 is the first substance in the steroid-synthetic pathway; it can be further metabolized into other steroids. Therefore, it is difficult to differentiate the roles of P5 versus its metabolites in the brain. To alleviate this problem, we synthesized and screened a series of non-metabolizable P5 derivatives for their ability to polymerize microtubules similar to P5. Results We identified compound #43 (3-beta-pregnenolone acetate), which increased microtubule polymerization. We showed that compound #43 modified microtubule dynamics in live cells, increased neurite outgrowth and changed growth cone morphology in mouse cerebellar granule neuronal culture. Furthermore, compound #43 promoted the formation of stable microtubule tracks in zebrafish developing cerebellar axons. Conclusions We have developed compound #43, a nonmetabolized P5 analog, that recapitulates P5 functions in vivo and can be a new therapeutic candidate for the treatment of neurodevelopmental diseases.

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Structure–activity relationship (SAR) analysis of a family of steroids acutely controlling steroidogenesis

Cited by 12 publications

References 35 publications

Translocator protein-mediated pharmacology of cholesterol transport and steroidogenesis

Translocator protein-mediated pharmacology of cholesterol transport and steroidogenesis

Drug Ligand-Induced Activation of Translocator Protein (TSPO) Stimulates Steroid Production by Aged Brown Norway Rat Leydig Cells

A synthetic pregnenolone analog promotes microtubule dynamics and neural development

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