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At least 217 records · Page 12Linked to original sources
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↗
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↗
PubMedDate not supplied

Inhibition of pyridine-nucleotide-dependent enzymes by pyrazoles. Synthesis and enzymology of a novel A-ring pyrazole steroid.

A novel A-ring pyrazole steroid, 2,3-bisaza-A-nor-1,5(10)-estradien-17 beta-ol (3), was synthesized as a potential inhibitor of steroidal NAD(P)H-dependent oxidoreductases. Compound 3 proved to be a potent inhibitor of 3(17)beta-hydroxysteroid dehydrogenase (from P. testosteroni) exhibiting a Ki of 90 +/- 20 nM. The activities of 3 alpha,20 beta-hydroxysteroid dehydrogenase (from S. hydrogenans), steroid-5 alpha-reductase (from rat prostate), and 3 alpha-hydroxysteroid dehydrogenase (from rat liver) were unaffected by pyrazole 3. Dead end inhibition studies indicate an ordered binding of cofactor prior to substrate or pyrazole inhibitor.

3-Hydroxysteroid Dehydrogenases↗
PubMedDate not supplied

Synthesis of 12-mono- and di-substituted 8-aza-11-oxasteroids.

The synthesis of unsaturated derivatives of 8-aza-11-oxa-17-oxo-gonane and D-homo-gonane carrying one or two functional substituents at C-12 is reported. The key step for the construction of the heterosteroid skeleton was the cyclocondensation reaction of aldol adducts 1, derived from 1,3-cycloalkanediones and diethyl 2-oxo-malonate, with tosyl chloride and isoquinoline.

Azasteroids↗
PubMedDate not supplied

Intermediates of stigmasterol metabolism in Spodoptera littoralis.

Stigmasterol-24,28-epoxide, 22E-stigmasta-5,22,24(28E)-trien-3 beta-ol, and 22E-cholesta-5,22,24-trien-3 beta-ol were identified as normal metabolites of [3H]stigmasterol in Spodoptera littoralis larvae. Relative concentrations of all three of these metabolites increased when a diazasterol inhibitor was fed in combination with stigmasterol in the artificial diet. Identification of these sterols as intermediates in the conversion of stigmasterol to cholesterol in this insect indicates that intermediates analogous to fucosterol and fucosterol-24,28-epoxide in the conversion of sitosterol to cholesterol are produced in the metabolism of stigmasterol. This is the first published identification of stigmasterol-24,28-epoxide and 22E-stigmasta-5,22,24(28E)-trien-3 beta-ol as intermediates in this pathway in an insect.

Animals↗
PubMed1991

Testosterone processing by pituitary cells in culture: an examination of the role of 5 alpha-reduction in androgen action on the gonadotroph.

Dispersed rat pituitary cells were exposed to [1,2,6,7-3H]testosterone ([3H]T, 10(-8) M) to assess the role of 5 alpha-reduction in T regulation of gonadotroph secretion. After 4 to 48 hours of exposure, [3H]T metabolites isolated by thin-layer chromatography were characterized in medium and cell homogenates as well as bound to androgen receptors salt-extracted from purified nuclear pellets. Receptor-bound 5 alpha-[3H]dihydrotestosterone ([3H]DHT)/total [3H]androgens rose progressively from 16% at 4 hours to more than 50% at 48 hours. Coincubation with 4-MA (10- to 1,000-fold molar excess) or testosterone-17 beta-carboxylic acid (TCA; 1,000-fold excess) reduced receptor-bound [3H]DHT/[3H]androgen to less than 10% and 20%, respectively, but elevated [3H]T-receptor levels. Despite inhibiting 5 alpha-reductase activity, TCA and 4-MA had no effect on T suppression of gonadotropin-releasing hormone-stimulated luteinizing hormone secretion or T enhancement of total (cell + secreted) follicle-stimulating hormone levels. The results suggest that 5 alpha-reduction to DHT is not essential for the expression of the direct influences of T on gonadotropin synthesis and secretion in rat gonadotrophs.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1993

Synthesis of novel 6-aza-B- and 11-aza-C-homoestranes as antifertility agents.

Reaction of 3,9 alpha, 17 beta-trihydroxyestra-1,3,5(10)-trien-11-one 17-acetate 3-methyl ether (3) with N3H-BF3 etherate leads mainly to lactam (4) along with the N-azido compound (5) as a minor product. Under similar conditions, 3,17 beta-dihydroxyestra-1,3,5(10)-trien-6-one 17-acetate 3-methyl ether gives lactam (12) and the tetrazole derivative (9). Similar reaction of the diacetate (8) gives only the tetrazole derivative (11). Compounds 4, 6, and 10 prevent implantation in rats at 5-, 10-, and 5-mg/kg doses, respectively. Compounds 4, 6, 9, and 10 show significant estrogenic activity at the respective contraceptive doses.

Animals↗
PubMed1995

The enzyme and inhibitors of 4-ene-3-oxosteroid 5 alpha-oxidoreductase.

Since evidence of 5 alpha-reductase activity in rabbit liver homogenate was discovered in 1954, the presence of this enzyme has been demonstrated in many other organs and tissues of mammalian species. 5 alpha-Reductase selectively transforms a 4-ene-3-oxosteroid (e.g., testosterone) irreversibly to the corresponding 5 alpha-3-oxosteroid (e.g., 5 alpha-dihydrotestosterone) in the presence of NADPH as an essential coenzyme at an optimal pH. However, excessive production of 5 alpha-dihydrotestosterone is the major cause of many androgen-related disorders, such as prostate cancer, benign prostatic hyperplasia, acne, female hirsutism, and male pattern baldness; therefore, inhibition of androgenic action by 5 alpha-reductase inhibitors is a logical treatment. During the past two decades, research has focused on understanding the biological functions and effects of 5 alpha-reductase and its 5 alpha-reduced metabolites: purification of the enzyme, substrates, and metabolites; characterization of their physical, chemical, and biochemical properties; analysis of the amino acid sequence of the enzyme; synthesis of various classes of molecules as potential inhibitors; and examination of the biological activity of the inhibitors in vitro and/or in vivo. This review summarizes the biochemical studies on this enzyme, suggests the mechanisms of action of the enzyme or inhibitors, and discusses the chemistry necessary for the preparation, structure-activity relationships, and in vitro and/or in vivo data obtained from the evaluation of nonsteroidal and steroidal compounds that have been tested as inhibitors of 5 alpha-reductase. In particular, IC50 and Ki values for relevant compounds will be compared according to molecular class. This review could function as a comprehensive working reference of what research has been accomplished so far and what problems remain to be solved in the future for those engaged in this interesting field.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1995

Synthesis of novel intranuclear diazasteroids.

By use of the aza Diels-Alder reaction a series of aminoisoquinolines and aminoquinolines have been elaborated to provide an effective synthesis of diverse diazasteroids. In particular, representative 1,11-diaza-, 3,11-diaza-, and 4,11-diazasteroids have been synthesized from cyclopentadiene. From dihydropyran a 4,11-diaza-15-oxa-D-homosteroid has been obtained.

Aminoquinolines↗
PubMed1990

The role of metabolism and covalent binding in the cytotoxicity of a nitrogen-containing steroid toward rat hepatocytes.

The nitrogen-containing steroid N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (I) causes concentration- and time-dependent cytotoxicity toward freshly isolated F-344 rat hepatocytes. Because hepatocytes extensively metabolize I to both stable and reactive products, the role of metabolism and covalent binding in the cytotoxicity of I was investigated. Concentration-dependent covalent binding of I-related material to hepatocyte macromolecules was detected. Treatment of rats with phenobarbital increased the rate and extent of hepatocyte metabolism of I, increased the covalent binding of I-related material to hepatocyte macromolecules, but decreased the cytotoxicity of I. Addition of testosterone to incubations of hepatocytes and I inhibited the metabolism of I, decreased the covalent binding of I-related material to hepatocyte macromolecules, but potentiated the cytotoxicity of I. These results indicate that the covalent binding of reactive metabolites is not involved in the cytotoxicity of I. Moreover, the two major metabolites of I, the 4-carbinolamide and monoethyl analog, were much less cytotoxic toward hepatocytes than I. These data suggest that the metabolism of I represents detoxication and that the parent compound is the cytotoxicant.

Animals↗
PubMed1991

A steroid derivative (RU 5135) exhibits epileptogenicity in the presence of deficient blood-brain barrier.

A hypothesis was tested that epileptic spiking, induced by systemic administration of a steroid derivative (RU 5135), may be associated with surgery-related cortical damage rather than epileptogenicity of the agent. Cumulative doses of the drug were given to rats and rabbits. The lasting quasi-periodic seizure discharges were always seen initially only under an epicortical electrode implant. Brain damage in inflicted by such an electrode was confirmed anatomically (by assessing the area of lesion) and noninvasively (by showing contrast-induced enhancement of CT brain images in the hemisphere homolateral to epicortical electrodes). The threshold of epileptic spiking varied inversely with the area of cortical damage inflicted by the electrode. In a number of cases no spiking was obtained from the hemisphere with nonpenetrating (intraosteal) electrodes. We caution that a breach of the BBB caused by conventional surgery in rodents can make a benign drug appear as excessively toxic thereby discrediting potentially useful compounds.

Androstanes↗