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At least 199 records · Page 11Linked to original sources

PubMed1982

Inhibition of steroid 5 alpha-reductase from human skin fibroblasts by 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one.

The capacity of 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (DMAA) to inhibit competitively steroid 5 alpha-reductase has been confirmed in human foreskin fibroblasts. The inhibitor works equally well in homogenates and in intact cells, is rapidly reversible, does not influence the amount of the enzyme, is equally effective in inhibiting the 5 alpha-reduction of testosterone, 4-androstene-3,17-dione, 20 alpha-hydroxy-4-pregnen-3-one and cortisol, and appears to be weakly bound to serum protein. The inhibitor is particularly effective (apparent Ki of approximately 3 nM) at the optimal pH of the enzyme (pH 5.5) and has no effect in the alkaline range (pH 9.0). DMAA appears to be a steroid that will be useful in the investigation of 5 alpha-reduction of steroid hormones in intact animals and in embryos.

17-Hydroxysteroid Dehydrogenases↗

PubMed1983

Inhibition by a 4-methyl-4-aza-steroid of NADPH: delta 4-3-oxosteroid-5 alpha-oxido-reductase activity in cultured interstitial cells derived from immature rat testis.

Prepubertal rat testes have high 5 alpha-reductase (delta 4-3-oxosteroid 5 alpha-oxidoreductase) activity and secrete various 5 alpha-reduced androgens. We demonstrate that Na-4-methyl-4-aza-3-oxo-5 alpha-pregnane-20 (S)-carboxylate, a potent inhibitor of the prostatic 5 alpha-reductase, competitively inhibits the microsomal 5 alpha-reductase of rat testis. The apparent Ki for testosterone is 3.5 nM. At a concentration of 5 X 10(-7) M this compound efficiently inhibits the 5 alpha-reductase in cultured interstitial cells derived from prepubertal rats. Testosterone and 4-androstene-3,17-dione are the major androgens produced by these cells in the presence of inhibitor. It is concluded that 4-methyl-4-aza-steroids are a useful tool in the study of steroid secretion by prepubertal Leydig cells.

5-alpha Reductase Inhibitors↗

PubMed1984

Metabolism of testosterone to 17 beta-hydroxy-5 alpha-androstane-3-one and 5 alpha-androstane-3 alpha, 17 beta-diol in alveolar macrophages from rat lung.

5 alpha-Reduction of testosterone was observed in lung cells obtained by bronchoalveolar lavage (greater than 95% macrophages) from the rats. This activity was inhibited by progesterone and corticosterone. Production of 17 beta-hydroxy-5 alpha-androstane-3-one and 5 alpha-androstane-3 alpha, 17 beta-diol from testosterone was higher in rat pulmonary alveolar macrophages than by the 800 g supernatant fraction of whole lung homogenate from the same animals. Alveolar macrophages from rats treated with the 5 alpha-reductase inhibitor 17 beta-N,N-diethylcarbamoyl-4-aza-4-methyl-5 alpha-androstane-3-one (5 mg/100 g b.w., s.c.) showed decreased metabolism of testosterone to 17 beta-hydroxy-5 alpha-androstane-3-one and 5 alpha-androstane-3 alpha, 17 beta-diol 4 h after treatment. This metabolism was also decreased in alveolar macrophages from rats exposed to potassium dichromate by intratracheal instillation. When bovine alveolar macrophages were incubated with potassium dichromate, 5 alpha-reduction of testosterone decreased significantly. The function of steroid 5 alpha-reduction in alveolar macrophages is currently not known.

Androstane-3,17-diol↗

PubMed1986

The effects of diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA) and (4R)-5,10-SECO-19-norpregna-4,5-diene-3,10,20-trione (SECO) on androgen biosynthesis in the rat testis and epididymis.

We have investigated the effects of two 4-ene-steroid 5 alpha-reductase inhibitors, diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA) and (4R)-5,10-seco-19-norpregna-4, 5-diene-3,10,20-trione (SECO), on testicular and epididymal androgen biosynthesis. Kinetic analyses revealed that both compounds inhibited epididymal DHT biosynthesis. 4-MA was a competitive inhibitor of epididymal nuclear and microsomal 4-ene-steroid 5 alpha-reductases (3-oxo-5 alpha-steroid: NADP 4-ene-oxidoreductase EC 1.3.1.22) with Kiapp values of 12.8 and 15.1 nmol/l compared to the respective Kmapp values of 185 and 240 nmol/l. Values for the Vmaxapp were always within 70-130% of the control. SECO at 1.0 mumol/l, also inhibited epididymal nuclear and microsomal 4-ene-steroid-5 alpha-reductases, causing respectively 2.9 and 5.2-fold increases in Kmapp. The Vmaxapp values were unchanged. However, SECO concentrations of 5 and 25 mumol/l abolished 4-ene-steroid 5 alpha-reductase activity at all testosterone concentrations. To examine the specificity of these compounds, we investigated their effects on the enzymes that convert pregnenolone to testosterone. Rat testis microsomes converted pregnenolone to testosterone via the 4-ene-3-oxo pathway, with the major metabolites being progesterone, 17-hydroxyprogesterone, 4-androstenedione and testosterone; some 17-hydroxypregnenolone was also formed. Very small amounts of dehydroepiandrosterone (DHA) and 5-androstenediol were detected. SECO, at a concentration that completely inhibited epididymal 4-ene-steroid 5 alpha-reductase activity, did not alter the metabolic profile of pregnenolone metabolism. However, 4-MA prevented the appearance of 4-ene steroids, and large quantities of 17-hydroxypregnenolone and DHA accumulated, suggesting that inhibition of the 3 beta-hydroxysteroid: NAD(P)+ oxidoreductase (EC 1.1.1.51) and 3-oxosteroid 5-ene-4-ene-isomerase (EC 5.3.3.1) [3 beta-hydroxysteroid dehydrogenase-isomerase] was occurring. Optimal conditions for the microsomal conversion of DHA to 4-androstenedione were determined; kinetic analyses of the 3 beta-hydroxysteroid dehydrogenase-isomerase activity revealed that 4-MA inhibited this reaction non-competitively, reducing Vmaxapp values to 25% of the control. The Kiapp determined from the intercept replot, was 121 nmol/l, and the Kmapp was always between 90 and 130% of the control value. It is concluded that SECO is more specific than 4-MA in its effects on androgen biosynthesis in the testis and epididymis and that both these drugs should provide useful tools in assessments of the relative contributions of 5 alpha-reduced androgens to androgen dependent processes.

Androgens↗

PubMed1989

Inhibition and time-dependent inactivation of human placental aromatase by 3-oxo-17 beta-carboxamido steroids.

Several N,N-dialkyl-3-oxo-4-aza-17 beta-carboxamido steroids were found to be competitive inhibitors versus androstenedione (AND) and time-dependent inactivators of aromatase activity from human term placental microsomes. Inhibition constants (Kis) from dead-end inhibition analyses indicated interactions between these compounds and the enzyme over a 0.8-7 microM inhibitor concentration range. The affinity of these compounds for aromatase leading to the time-dependent loss of enzyme activity was several fold higher than that estimated by the steady-state kinetics, with rate constants of inactivation of 0.025-0.033 min-1. 3-Oxo-4-aza steroids lacking a 17 beta-carboxamide were found to be competitive inhibitors of AND for aromatase, but did not inactivate enzyme activity in a time-dependent manner. Steroids which did not contain a 4-aza substituent, but retained the 17 beta-carbamoyl functionality, were both inhibitors and inactivators of aromatase activity in the microsomes. The time-dependent loss of aromatase activity induced by these compounds was shown to require reducing equivalents as provided by NADPH. Hence, it is suggested that the inactivation of aromatase by compounds in this series is dependent on enzymatic activation in the presence of the N,N-dialkyl-17 beta-carbamoyl substituent.

Androstenedione↗

PubMed1989

Cobalt-protoporphyrin, a synthetic heme analogue, feminizes hepatic androgen metabolism in the rat.

A single injection of cobalt-protoporphyrin (50 mumol/kg) produced marked changes in the metabolism of 14C-labeled testosterone and 4-androstenedione by male rat liver microsomes and this effect was maintained for at least 3 weeks. The rate of 3 beta- and 5 alpha-reduction was increased to levels observed in untreated adult female animals and cobalt-protoporphyrin altered the metabolic profile of testosterone towards that observed after infusion of growth hormone whereas hypophysectomy produced a more general inhibition of androgen metabolism. The reduction of testosterone or 4-androstenedione by liver microsomes was also increased when cobalt-protoporphyrin (10-30 microM) was added in vitro but a higher concentration (100 microM) led to inhibition of androgen metabolism. The identity of the main androgen metabolites was established by TLC, HPLC and mass spectrometry and the role of 5 alpha-reductase was demonstrated using a specific inhibitor of this enzyme. The possible sites of action of cobalt-protoporphyrin are discussed in relation to its in vivo effects on serum testosterone and LH concentrations.

5-alpha Reductase Inhibitors↗

PubMed1989

Photoaffinity labelling of nuclear steroid 5 alpha-reductase of rat ventral prostate.

In order to get more information on the molecular structure of the rat prostatic 5 alpha-reductase (3-oxo-5 alpha-steroid: NADP+ 4-ene-oxidoreductase, EC 1.3:1.22) a systematic photoaffinity labelling study has been performed. To irreversibly freeze the status quo of interaction, either testosterone, the physiological ligand, or diazo-MAPD (21-diazo-4-methyl-4-aza-5 alpha-pregnane-3,20-dione), a specific 5 alpha-reductase inhibitor, was irradiated with isolated nuclei or with purified nuclear membranes or with solubilized nuclear membrane proteins and checked for optimal labelling conditions. The principal substances covalently labelled were phospholipids and at a minor ratio proteins. Analysis by SDS-PAGE and autoradiofluorography revealed two labelled polypeptides with molecular weights of 20 kDa and 26 kDa. The following evidence indicates that these polypeptides might be derived from the enzyme 5 alpha-reductase: both proteins are labelled only when specific ligands for 5 alpha-reductase are used; binding can be reduced by the addition of an excess of unlabelled ligand; enzyme activity is irreversibly suppressed when irradiated in the presence of these ligands; only subcellular fractions containing 5 alpha-reductase reveal the labelled proteins; in all 5 alpha-reductase containing preparations with increasing specific activity, independent of the polypeptide pattern, the same proteins are labelled.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1990

Regulation of 5 alpha-reductase activity in cultured immature leydig cells by human chorionic gonadotropin.

The present studies examined the hormonal regulation of 5 alpha-reductase activity in cultured immature rat Leydig cells. Within the testis 5 alpha-reductase was concentrated in the interstitial cell compartment, and among interstitial cells, the enzyme was localized primarily in Band 3 of Percoll density gradients, which contains the majority of Leydig cells. Among various factors reported previously to stimulate testicular 5 alpha-reductase activity when administered in vivo to immature rats (LH/hCG, FSH, luteinizing hormone releasing hormone or prolactin), only LH/hCG directly stimulated 5 alpha-reductase activity of cultured immature Band 3 cells. Neither growth hormone which was reported previously to stimulate hepatic 5 alpha-reductase activity, nor insulin, insulin-like growth factor-I, or epidermal growth factor, which have been reported to modulate Leydig cell function, had any effect on 5 alpha-reductase activity of Band 3 cells. These studies suggest that the major factor directly stimulating 5 alpha-reductase activity in Leydig cells during early maturation is LH. However, it is possible that other factors acting indirectly may modulate the maturational rise in 5 alpha-reductase activity.

3-Hydroxysteroid Dehydrogenases↗

PubMed1984

RO5-4864 inhibits the binding of [35S]t-butylbicyclophosphorothionate to rat brain membranes.

RO5-4864, a 1,4-benzodiazepine, has recently been shown to possess anticonvulsant, convulsant and anxiogenic properties and to inhibit Ca++-calmodulin-stimulated membrane phosphorylation. RO5-4864 inhibited the binding of [35S]t-butylbicyclophosphorothionate (TBPT) to cerebral cortex, cerebellar and hippocampus membranes, with an IC50 value of approximately 20 microM. TBPT binds apparently to the picrotoxinin site of the benzodiazepine-GABA receptor-ionophore complex and appears to be a site of action for several classes of convulsant, depressant and anxiolytic drugs that modulate GABAergic transmission. RO5-4864 inhibited [35S] TBPT binding in cerebral cortex, apparently competitively. Antagonists of GABA and central benzodiazepine sites did not interfere with the ability of RO5-4864 to inhibit [35S] TBPT binding. The properties of RO5-4864 to inhibit TBPT binding are similar to other convulsants and GABA antagonists (except bicuculline) which inhibit TBPT binding. These results suggest that RO5-4864 interacts with the TBPT binding sites of the oligomeric GABA receptor complex.

Androstanes↗

PubMed1984

Similar properties of [35S]t-butylbicyclophosphorothionate receptor and coupled components of the GABA receptor-ionophore complex in brains of human, cow, rat, chicken and fish.

No significant differences are evident in the specific binding characteristics of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) to EDTA/water-dialyzed P2 membranes of human, cow, rat, chicken and fish brain. This species similarity includes dissociation constants of 61-77 nM at 37 degrees C, maximum receptor densities of 3-7 pmol/mg protein, and sensitivity to inhibition or displacement by gamma-aminobutyric acid (GABA), two cage convulsants (picrotoxinin and t-butylbicycloorthobenzoate) and the insecticide [1R,cis, alpha S]-cypermethrin, indicating a constancy during vertebrate evolution of the [35S]TBPS binding site and its coupling with other components of the GABA receptor-ionophore complex. As a possible exception, chicken and fish brain membranes appear to be less sensitive than the others to the insecticide alpha-endosulfan. Human and rat preparations are also essentially identical relative to the inhibition of radioligand binding by two GABA mimetics (muscimol and 3-amino-propanesulfonic acid), six other cage convulsants (including examples of three classes of polychlorocycloalkane insecticides), a potent anthelmintic agent (Ivermectin), dimethylbutylbarbiturate, the convulsant benzodiazepine Ro 5-3663, and ethanol. The findings to date with [35S]TBPS and the GABA receptor-ionophore complex in rat brain membranes are therefore generally applicable to human preparations. Cow brain is an appropriate source for large scale preparations in receptor purification studies since it is essentially identical to human and rat preparations in all parameters examined. Species differences in sensitivity to the toxic effects of the convulsants and polychlorocycloalkane insecticides considered are apparently not attributable to receptor site specificity.

Androstanes↗

PubMed1994

5 alpha-reduced progesterone metabolites are essential in hamster VTA for sexual receptivity.

Progesterone's (P) actions in the ventral medial hypothalamus (VMH) and the ventral tegmental area (VTA) are essential for sexual receptivity in hamsters. This study investigates the notion that P works in the VTA in the absence of intracellular P receptors (PRs) by 5 alpha-reduction to progestins, which would subsequently bind to membrane gamma-Aminobutyric Acid receptor complexes (GBRs). To test the importance of P metabolism, a 5 alpha-reductase inhibitor, 17 beta-N, N-diethylcarbamoyl-4-methyl-4aza-5 alpha-androstan-3-one (4MA) was administered SC (0, 3, 9, 15, 24, or 30 mg/kg) to ovx estradiol benzoate(EB)-primed hamsters, followed by one of six doses of SC P (0, 25, 50, 100, 200, or 500 micrograms) and sexual receptivity testing. 200 micrograms P-treated animals administered higher (24 and 30 mg/kg) doses of 4MA had significantly decreased total lordosis durations (TLDs) compared to 0 mg/kg 4MA controls (exp 1). In exp 2, 4MA was aimed bilaterally at the VTA prior to SC P. After 200 micrograms P, animals had significantly lower TLDs than after 500 micrograms P, 3 hours following bilateral VTA implantation of 4MA, but not cholesterol. In exp 3, cycling female hamsters were infused with 1.0 microgram 4MA or vehicle unilaterally into the VTA on diestrus, proestrus, and estrus. 4MA, but not vehicle, infusions into the VTA interrupted receptivity in estrus and proestrus animals, but had no effect on diestrus animals. 4MA's reduction of receptivity when given systemically and intracranially strongly supports the hypothesis that 5 alpha-reduced P metabolites, possibly interacting with GBRs in the VTA, are essential for sexual receptivity in hamsters.

5-alpha Reductase Inhibitors↗

PubMed1990

High-density lipoprotein response to 5-alpha-dihydrotestosterone and testosterone in Macaca fascicularis: a hormone-responsive primate model for the study of atherosclerosis.

A decrease in high-density lipoprotein cholesterol (HDL-C), a major risk factor for coronary artery disease, occurs during puberty in males. Previous studies have shown this decrease with testosterone (T) therapy for adolescent males, but the mechanism of this effect is unknown and has not been studied in a non-human primate. Two adult male monkeys (Macaca fascicularis) were studied to determine simultaneous changes in plasma androgens and HDL-C during the phases precastration (Ci); postcastration (Cx); Cx and T therapy; Cx and dihydrotestosterone (DHT) therapy; and T and 5-alpha-reductase inhibitor therapy (4-MA). After castration, the HDL-C concentrations increased significantly in both animals (monkey A, 57.0 +/- 1.8 mg/dL SE to 66.6 +/- 2.2, P less than .005; monkey B, 62.9 +/- 1.6 to 80.2 +/- 1.7, P less than .001). T-propionate treatment produced a significant decrease in HDL-C (monkey A, 48.0 +/- 5.0, P less than .01; monkey B, 43.5 +/- 0.5, P less than .001), which was similar to HDL-C reductions seen when treated with a nonaromatizeable androgen, DHT-propionate (monkey A, 47.5 +/- 1.5, P less than .005; monkey B, 44.5 +/- 3.5, P less than .001). T and the 5-alpha-reductase inhibitor therapy did not increase HDL-C from the levels with T therapy alone (monkey A, 55.7 +/- 1.9, NS; monkey B, 57.3 +/- 0.3, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

5-alpha Reductase Inhibitors↗

PubMed1993

Induction of chromosomal aberrations in human lymphocytes by the antitumour alkylating agent homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenoxy acetic acid, in vitro.

The clastogenic activity of the antineoplastic alkylating agent 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam- p-bis (2-chloroethyl) aminophenoxy acetic acid (NSC 294859) and its congeners was studied in human lymphocyte cultures in vitro. Cells were exposed to several concentrations of the drugs for 24 h. It was found that NSC 294859 reduces the mitotic index and causes chromosome- as well as chromatid-type aberrations in a dose-dependent way. From its congeners, the alkylating agent (p-bis(2-chloroethyl)aminophenoxy acetic acid) induces the same phenomena but to a lesser extent, while the modified steroid (3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam) causes cytogenetic damages at the control level. These results favour the assumption that the antitumour activity of NSC 294859 is mainly based on its cytogenetic effects.

Alkylating Agents↗

PubMed1981

A steroid derivative, R 5135, antagonizes the GABA/benzodiazepine receptor interaction.

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Androstanes↗

PubMed1983

Regular and lasting neocortical spiking produced by systemic administration of a steroid derivative in the rat.

The hypothesis was tested that sedation and stereotyped behaviour, developing in rats after the administration of the steroid derivative with gamma-aminobutyric acid (GABA) antagonistic properties, R 5135, are of an epileptiform nature. Electroencephalographic (EEG) and visual evoked potentials (VEP) were recorded and behaviour was observed over not less than 5-7 hr after subconvulsive doses of R 5135. Doses of 2-4 mg/kg of the compound produced quasi-rhythmic spikes resembling experimental focal epileptic discharges in all rats. This epileptiform activity was accompanied by behavioural sedation and somnolence, followed by a build-up of stereotyped behaviour and sporadic episodes of epileptiform motor activity, developing 1-2 hr after injection. The secondary components (SNW) of the visual evoked potentials were suppressed by R 5135 and the primary potential (N1) facilitated, virtually reducing the visual evoked potential to the form of an evoked spike. Pretreatment with the anticonvulsant GABAergic drugs gamma-acetylenic GABA (GAG) (100 mg/kg), sodium valproate (VPA) (400 mg/kg) and diazepam (5 mg/kg) suppressed the motor components of seizure activity, producing severe ataxia, but not the electrographic manifestation of seizure activity. Neither gamma-acetylenic GABA nor valproate significantly altered the latency to onset of spiking, although all three drugs did significantly reduce the frequency of discharges. Diazepam was the only anticonvulsant tested which completely suppressed spike activity in 3 of 5 rats. Moreover, R 5135 was found to antagonize diazepam, but not valproate induced suppression of secondary components of the visual evoked potential, suggesting that diazepam and R 5135 may compete for the same receptor.

Action Potentials↗

PubMed1983

Effects of an anti-androgen and 5 alpha-reductase inhibitors on estrus duration in the cycling female rat.

Five experiments examined the role of circulating androgens in the control of sexual behavior (lordosis) in the intact cycling rat. The androgen receptor blocker, flutamide (FLU), was administered daily to cycling rats beginning on the day of estrus, and lordotic responsiveness was measured on the 2nd subsequent proestrus day and on the day of estrus. FLU-treated females showed significantly higher levels of lordosis throughout the end of the period of estrus than controls (Experiment 1). Neither the maximal levels of lordosis seen on the evening of proestrus nor the time of onset of estrous responsiveness during the preceeding afternoon were affected by FLU (Experiment 2). Serum estradiol concentrations seen on the morning of proestrus (Experiment 3) did not differ between FLU- and vehicle-treated animals. The weak 5 alpha-reductase inhibitor, testosterone-17 beta-carboxylic acid (17 beta C), prolonged slightly, but did not significantly lengthen, the period of estrus (Experiment 4), while the highly potent steroidal 5 alpha-reductase inhibitor, 4 MA, significantly increased the rate at which estrous behavior declined on the day of estrus (Experiment 5). Circulating androgens do not appear to affect the maximal level of sexual receptivity displayed nor the time of estrus onset; however, they may govern the duration of the period of estrus by influencing the rate of estrus termination.

Anilides↗

PubMed1976

Total synthesis of diazasteroids (1).

Contrary to previous reports, the condensation product of 8-aminoquinoline (1) and 2-carbethoxycyclopentanone (2) undergoes ring closure with polyphosphoric acid to give the 1, 11-diazasteroid 5. Catalytic hydrogenation reduced the A ring and the double bond to produce 6. 8-Aminotetrahydroquinoline (7) and 3-carbethoxy-2-piperidone condense to a tricyclic intermediate (11), which could not be cyclized to a steroid, however.

Aminoquinolines↗

PubMed1976

Syntheses and ultraviolet absorption of aza-steroids.

A series of aza-steroids was synthesized containing chromophoric groups, such as a, beta-unsaturated ketones and doubly unsaturated conjugated and monoconjugated heteroannular dienones with the heteroatom in the D ring at the 20 and 17a positions. The effect of an appositely placed electronegative center in these molecules upon their ultraviolet absorptions was studied. In order to obtain a basis for the observed spectral changes, the corresponding carbocyclic compounds were also synthesized. The maximum absorptions of the aza-steroids were hypsochromically shifted relative to the carbocyclic compounds in all cases (n=8). The displacement caused by the electronegative center on absorption maximum of the chromophores is, however, highly dependent on its location within the molecules.

Azasteroids↗