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PubMed1993

Mono N-aryl ethylenediamine and piperazine derivatives are GABAA receptor blockers: implications for psychiatry.

Ethylenediamine (EDA) and piperazine are known GABA-A receptor agonists and this activity appears to reside in their carbamate adducts. In CO2-free incubation medium EDA and piperazine weakly reverse the inhibitory action of 1 microM GABA on specific [35S]t-butylbicyclophosphorothionate (35S-TBPS) binding to rat brain membranes in vitro. In 25 mM sodium bicarbonate buffer, EDA and piperazine much more potently inhibit 35S-TBPS binding in a way reversible by the GABA-A receptor blocker R5135. Thus, native EDA and piperazine are weak GABA-A receptor blockers, while their presumed carbamate adducts, formed by reaction with bicarbonate, are more potent GABA-A receptor agonists. Virtually all structural modifications of EDA or piperazine result in GABA-A receptor blockers, even in the presence of bicarbonate, judging from their abilities to fully or partially reverse the inhibitory effect of GABA on 35S-TBPS binding. Of 12 non-aromatic piperazine or EDA derivatives, the piperazine derivatives are the more potent GABA antagonists, although all are weak compared to the mono N-aryl derivatives. Nineteen mono N-aryl EDA derivatives are moderately potent GABA antagonists, including 10 with demonstrated or potential antidepressant activity. Most of the N-aryl piperazines are moderately to highly potent GABA antagonists, one (pitrazepin) being 4 to 5 times more potent than bicuculline. There are several clinically effective antidepressants (e.g. Amoxapine, Mianserine) and antipsychotics (Clothiapine, Loxapine, Metiapine, Clozapine and Fluperlapine) among the more potent N-aryl piperazine GABA antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Androstanes↗
PubMed1992

Consideration of the use of 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5- alpha-androstan-3-one (4MA), a 5 alpha-reductase inhibitor, in prostate cancer therapy.

We investigated the effect of 17 beta-N,N-diethylcarbamoyl-4-methyl-4aza- 5 alpha-androstan-3-one (4MA), a 5 alpha-reductase inhibitor, on growth inhibition of androgen-sensitive rat prostatic tumour (R3327-H) and correlated it with changes in weight of normal androgen target tissues and with levels of androgens. Groups of male Copenhagen rats were treated for 28 days with a daily injection of various, increasing doses of 4MA (0.01-4.0 mg/day) and the results were compared with control (vehicle-treated) and with castrated animals. 4MA decreased tumour growth rate in a dose-dependent manner, which was reflected in a decreased incorporation of BrdUrd in DNA of glandular epithelial cells in the tumour. Normal prostate wet weight was also decreased after high-dose 4MA treatment while serum testosterone levels were not affected by 4MA treatment. Contrary to expectations, however, tissue levels of dihydrotestosterone in tumour and ventral prostate were still considerable in 4MA-treated animals. The tumour-inhibiting action of 4MA, therefore, has to be interpreted as not being purely due to 5 alpha-reductase inhibition. On the other hand, it was not possible to demonstrate any direct tumoricidal effect of 4MA in vitro. The relevance of these findings in terms of the endocrine mechanism of action of 4MA on tumour growth is discussed.

5-alpha Reductase Inhibitors↗
PubMed1978

Sterols in yeast subcellular fractions.

Yeast is the most primitive organism synthesizing substantial amounts of sterols. Because of this eucaryotic organism's versatility in growth conditions, ease of culture, well-defined genetic mechanism, and characteristic subcellar architecture, it is readily applied to studies of the role of sterols in the general economy of the cell. Sterols exist in two major forms, as the free sterol, or esterified with long chain fatty acids. The importance of sterols for this organism can be demonstrated using a naturally occurring antimycotic azasterol. This agent inhibits yeast growth. Three effects are seen on sterol synthesis: inhibition of the enzymes delta14-reductase, sterol methyltransferase, and methylene reductase. Cells cultured on respiratory substrates are more sensitive to inhibition than are cells growing on glucose. We have demonstrated a relationship between respiratory competency and sterol biosynthesis in this organism. Many mutants altered in sterol synthesis are respirationally defective and must grow fermentatively. One clone has temperature conditional respiration. Experiments with purified mitochondria, prepared from this mutant and its isogenic wildtype, show that the mutant organism is able to respire at the higher temperature but lacks the ability to couple respiration to phosphorylation. No similar loss is seen in the wild-type clones. Data are given which support the proposal that, for inclusion in mitochondrial structures, yeast cells may discriminate among sterols available from the total sterol pool in favor of ergosterol.

Azasteroids↗
PubMed1977

Accumulation of ergosta-8,14-dien-3beta-ol by Saccharomyces cerevisiae cultured with an azasterol antimycotic agent.

15-Aza-25-methylene-D-homocholesta-8,14-dien-3beta-ol, an antimycotic agent, at a concentration of 75 ng/ml inhibited ergosterol biosynthetis in Saccharomyces cerevisiae strain 3701B resulting in the accumulation of an unusual sterol. Experimental data presented indicate that this sterol is ergosta-8,14-dien-3beta-ol. The accumulation of the compound is supportive of current models of biosynthetic pathways for sterols in yeast and is consistent with inhibition by the azasterol of the delta14 sterol reductase.

Antifungal Agents↗
PubMedDate not supplied

Pharmacokinetics and biochemical efficacy after single and multiple oral administration of N-(2-methyl-2-propyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide, a new type of specific competitive inhibitor of testosterone 5 alpha-reductase, in volunteers.

The pharmacokinetics and biochemical efficacy of N-(2-methyl-2-propyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (I) were evaluated in healthy male volunteers after single and multiple oral administration. The mean times to reach peak plasma concentrations (Tmax) of (I) at doses of 5, 10, 20, 50 and 100 mg ranged from 1.8 to 2.8 h, and the corresponding mean peak plasma concentrations (Cmax) were 38.1, 81.5, 147.1, 442.0 and 835.5 ng/ml, respectively. The drug disappeared from the systemic circulation with half-lives (t1/2) of 4.7-7.1 h. The mean values of the area under the curve (AUC0-24) and Cmax increased linearly in a dose-dependent manner. After multiple oral administration of (I) (10 mg/d) for 7 days, Cmax and AUC increased slightly during administration, however, there were no significant differences between day 4 and day 7. Although there were large intersubject differences in the 24 h plasma levels after each dosing, no accumulation of (I) occurred after 7 days dosing. Serum 5-alpha-dihydrotestosterone (DHT) was markedly reduced at all dose levels. The mean serum levels of DHT at 24 h post-dosing decreased to 27-42% of that before dosing. On the other hand, the serum testosterone (T) did not change significantly. After multiple administration of (I), serum DHT was significantly reduced and remained suppressed for up to 7 days after the final dosing.

5-alpha Reductase Inhibitors↗
PubMed1993

Lack of influence of aromatase and 5 alpha-reductase inhibition on [3H]imipramine binding in the male rat brain.

In intact adult male rats an inhibitor of aromatase and an inhibitor of 5 alpha-reductase did not change the characteristics of [3H]imipramine binding sites in cerebral cortex, hypothalamus, and hippocampus. Testosterone, estradiol and dihydrotestosterone prevented the effect of castration on the number of [3H]imipramine binding sites, but had no effect in non-castrated animals. These data suggest that testosterone and its major metabolites, estradiol and dihydrotestosterone, are equally effective with regard to imipramine binding sites.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2002

[Dihydrotestosterone and the role of 5 alpha-reductase inhibitors in benign prostatic hyperplasia].

The genesis of benign prostate hyperplasia (BPH) depends on two factors: testicular androgen and the aging process. The most important androgen in the prostate is dihydrotestosterone (DHT). In the aging male the level of DHT in the prostate remains largely constant although the plasma level of testosterone decreases. DHT is formed by the reduction of testosterone by the enzyme 5-alpha-reductase, which has two isoenzymes. The 5-alpha-reductase type 2 is the predominant isoenzyme in genital tissue and thus also in the prostate. Finasteride is a 5-alpha-reductase inhibitor, which is applied in the treatment of BHP and male baldness. In the doses used finasteride acts mainly by inhibiting the 5-alpha-reductase type 2, thereby reducing the serum level of DHT by approximately 70% and by about 85-90% in the prostate. Indeed the effect of finasteride in BPH was proven in clinical studies. However, the circulating and intraprostatic DHT could be further reduced by a more effective dual 5-alpha-reductase inhibitor, which would be efficacious in the treatment of benign prostate hyperplasia and other DHT-related disorders.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2004

[Chemoprevention of prostate cancer].

Despite advances in the detection and management of prostate cancer, this disease remains a major cause of morbidity and mortality in men. Increasing attention has focused on the role of chemoprevention for prostate cancer, i.e., the administration of agents that inhibit one or more steps in the natural course of prostate carcinogenesis. We review prostate cancer chemoprevention studies in Europe. Published studies were identified in a search of MEDLINE. Information about ongoing studies was provided by author access to protocols. A variety of chemoprevention studies have focused on the role of dietary factors, vitamins, and trace elements in prostate cancer. Some of these studies have been prospective, randomized, and double-blinded, while others have used retrospective or epidemiological approaches. Large-scale randomized studies are also evaluating the role of 5alpha-reductase inhibitors, which inhibit the conversion of testosterone to the more potent androgen dihydrotestosterone. Robust evidence is lacking for the value of chemopreventive agents in prostate cancer. Current evidence does suggest that vitamin E and selenium may have a role in prostate cancer chemoprevention. Data from two studies, one examining the type 1 5alpha-reductase selective inhibitor finasteride and the other using the dual 5a-reductase inhibitor dutasteride, will determine the benefits of androgen inhibition strategies for prostate cancer chemoprevention.

Anticarcinogenic Agents↗
PubMed2002

Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia.

The development of human benign prostatic hyperplasia (BPH) clearly requires a combination of testicular androgens and the ageing process. Although the role of androgens as the causative factor for human benign prostatic hyperplasia is debated, they undoubtedly play, at least, a permissive role. The principal prostatic androgen is dihydrotestosterone. Although not elevated in human benign prostatic hyperplasia, dihydrotestosterone levels in the prostate remain at a normal level with ageing, despite a decrease in the plasma testosterone. Dihydrotestosterone (DHT) is generated by a reduction in testosterone. Two isoenzymes of 5alpha-reductase have been discovered. Type 1 is present in most tissues in the body where 5alpha-reductase is expressed, and is the dominant form in sebaceous glands. Type 2 5alpha-reductase is the dominant isoenzyme in genital tissues, including the prostate. Finasteride is a 5alpha-reductase inhibitor that has been used to treat BPH and male-pattern baldness. At doses used clinically, its major effect is to suppress type 2 5alpha-reductase, because it has a much lower affinity for the type 1 isoenzyme. Finasteride suppresses DHT by about 70% in serum and by as much as 85%-90% in the prostate. The remaining DHT in the prostate is likely to be the result of type 1 5alpha-reductase. The suppression of both 5alpha-reductase isoenzymes with GI198745 results in greater and more consistent containment of serum dihydrotestosterone than that observed with a selective inhibitor of type 2 5alpha-reductase. Physiological and clinical studies comparing dual 5alpha-reductase inhibitors, such as GI198745, with selective type 2, such as finasteride, will be needed to determine the clinical relevance of type 1 5alpha-reductase within the prostate. There have been two large, international multicentre, phase III trials published documenting the safety and efficacy of finasteride in treating human benign prostatic hyperplasia. Combining these two studies, randomised, controlled data are available for 12 months. Non-controlled extension of these data from a subset of patients, who elected to continue on the drug for 3, 4 and 5 years, are also available. Long-term medical therapy with finasteride can reduce clinically significant endpoints, such as acute urinary retention or surgery. According to the meta-analysis of six randomised, clinical trials with finasteride, finasteride is most effective in men with large prostates. A more effective dual inhibitor of type 1 and 2 human 5alpha-reductase may lower circulating dihydrotestosterone to a greater extent than finasteride and show advantages in treating human benign prostatic hyperplasia and other disease states that depend on dihydrotestosterone. A clinical evaluation of potent dual 5alpha-reductase inhibitors may help to define the relative roles of human type 1 and 2 5alpha-reductase in the pathophysiology of benign prostatic hyperplasia and other androgen-dependent diseases.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2005

Effects of 5 alpha reductase inhibitors on androgen-dependent human prostatic carcinoma cells.

PURPOSE: To investigate the effects of MK906, a selective 5 alpha reductase (5alphaR) type 2 (5alphaR2) inhibitor, and of MK386, a specific 5alphaR1 inhibitor, on the cellular proliferation of androgen-dependent human prostatic cancer (PCa) cells in cultures of cells derived from bioptic and surgical tissues. METHODS: In this study we tested the effects of MK906 and MK386 in 30 cultures derived from PCa, 6 from PIN and 10 from benign prostatic hyperplasia specimens. RESULTS: Prostate primary cultures under short-term conditions (with <4 subcultures) represent a mixture of epithelial and stromal cells. Epithelial cells require testosterone (T) for optimal growth, but were not able to grow in the presence of T under long-term conditions even if DHT was able to induce cellular proliferation to a similar extent in both conditions, suggesting that 5alphaR can be lost in long-term cultures. Therefore, our studies were performed under short-term conditions. Both 5alphaR inhibitors decreased cell proliferation significantly and dose-dependently in all the samples tested. MK906 was more efficient than MK386 in 7 out of 10 cultures derived from BPH tissues, in 4 out of 6 cultures derived from PIN and in 18 out of 30 cultures derived from PCa. In 3 out of 10 BPH, in 2 out of 6 PIN and in 5 out of 30 PCa-derived cultures, both inhibitors presented similar efficacy, whereas in 1 out of 10 BPH and 7 out of 30 PCa-derived cultures MK386 was more efficient than MK906. In addition, MK386 was more efficient than MK906 in 4 out of 15 non-metastatic PCa and 2 out of 7 metastatic PCa-derived cultures. CONCLUSIONS: Considering that 5alphaR1 (responsible primarily for androgenic catabolism) is mostly expressed in epithelial cells and that 5alphaR2 (responsible for local DHT synthesis and release) is expressed in the stromal cells (which provides several paracrine growth factors and DHT itself to the epithelial cells), our experiments suggest that the inhibition of both 5alphaR1 and 5alphaR2 by MK386 and MK906, respectively, may have therapeutic potential in order to reduce the growth and progression of human prostatic cancers, through the inhibition of autocrine or paracrine mechanisms involving the stromal cell compartment. In addition, some effects of 5alphaR inhibitors could be mediated by estrogens, which are synthesized by the aromatase enzyme present in the epithelial cells. These aspects could be considered in order to improve the therapeutical management of PCa and for future clinical trials.

5-alpha Reductase Inhibitors↗
PubMed2005

Lactandrate: a D-homo-aza-androsterone alkylator in the treatment of breast cancer.

The sensitivity of breast neoplasms to hormonal control provides the basis of novel investigational treatments with steroidal alkylators. An androsterone D-lactam steroidal ester, the 3beta-hydroxy-13alpha-amino-13,17-seco- 5alpha-androstan-17-oic-13,17-lactam, p-bis(2-chloroethyl)amino phenyl acetate (lactandrate) was synthesized and tested for antitumor activity against six human breast cancer cell lines in vitro and against two murine and one xenograft mammary tumors in vivo. A docking study on the binding interactions of lactandrate with the ligand-binding domain (LBD) of estrogen receptor-alpha (ERalpha) was inquired. In vitro testing of lactandrate cytostatic and cytotoxic activity was performed on T47D, MCF7, MDA-MB-231, BT-549, Hs578T, MDA-MB-435 breast adenocarcinoma human cell lines. In vivo testing was performed on two murine mammary tumors, the MXT tumor and CD8F1 adenocarcinoma, as well as on human mammary carcinoma MX-1 xenograft. Molecular modeling techniques were adopted to predict a possible location and interaction mode of the molecule into LBD. Lactandrate induced significantly high antitumor effect against all tested in vitro and in vivo models. The cell lines with positive ER expression found to be significantly more sensitive to lactandrate. Moreover, lactandrate found to be positioned inside the binding cavity with its steroidal moiety, whilst the alkylating moiety protrudes out of receptor's pocket. Lactandrate produced important anticancer activity on breast cancer in vitro and in vivo. Some correlation between ER and lactandrate effect was demonstrated. Docking studies provide the basis for the structure-based design of improved steroidal alkylating esters for the treatment of estrogen-related cancers.

Adenocarcinoma↗
PubMed2006

Delayed fluorescence and phosphorescence of 8-aza-D-homogonane in the gas and condensed phases.

The delayed fluorescence spectrum for 8-aza-D-homogonane in the gas phase consists of a band of E-type delayed fluorescence of M-centers and a band of P-type delayed fluorescence of L-centers being the products of photo- and thermotransformations of a basic steroid. Triplet-triplet energy transfer from the M-centers to the L-centers is established and its efficiency is determined. For 8-aza-D-homogonane in frozen hexane solutions at T=77 K only the phosphorescence of the M- and L-centers is revealed. The phosphorescence of the basic steroid itself (lambda(max)(phos) = 415 nm) as well as that of the M- and L-centers (lambda(max)(phos) = 498 and 532 nm, respectively) is seen in a mixture of frozen tetrahydrofuran and toluene solutions. This is evident of the fact that the basic steroid has the products of its transformations, whose amount grows due to irradiation and heating. The M- and L-centers are stable molecules.

Azasteroids↗
PubMed2004

The role of 5-alpha-reductase inhibition as monotherapy in view of the MTOPS data.

Medical treatment for the symptoms of benign prostatic hyperplasia (BPH) consists of a blockers and 5-alpha-reductase inhibitors. Data suggest that 5-alpha-reductase inhibitors can prevent progression of BPH and reduce the risk of BPH-related surgery, especially in men with large-volume prostates. Results from the largest randomized, prospective, placebo-controlled trial, the Medical Therapy of Prostatic Symptoms trial, have been presented. These results support the notion of using 5-alpha-reductase inhibitors for the prevention of BPH progression and BPH-related surgery. Furthermore, long-term 5-alpha-reductase inhibitor monotherapy, although slow in onset, is a viable therapy for symptom relief in men with mild to moderate symptoms.

5-alpha Reductase Inhibitors↗
PubMed1988

Inhibition of steroid 5 alpha-reductase and its effects on testosterone hydroxylation by rat liver microsomal cytochrome P-450.

It has been shown previously that liver microsomal steroid 5 alpha-reductase activity increases with age in female but not male rats, which coincides with a female-specific, age-dependent decline in the cytochrome P-450-dependent oxidation of testosterone to 1 beta-, 2 alpha-, 2 beta-, 6 alpha-, 6 beta-, 7 alpha-, 15 beta-, 16 alpha-, 16 beta-, and 18-hydroxytestosterone and androstenedione. To determine whether the increase in steroid 5 alpha-reductase activity is responsible for the decrease in testosterone oxidation, we have examined the effects of the steroid 5 alpha-reductase inhibitor, 4-MA (17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one), on the pathways of testosterone oxidation catalyzed by rat liver microsomes. We have also determined which hydroxytestosterone metabolites are substrates for steroid 5 alpha-reductase. At concentrations of 0.1 to 10 microM, 4-MA completely inhibited steroid 5 alpha-reductase activity without inhibiting the pathways of testosterone oxidation catalyzed by liver microsomes from rats of different age and sex, and from rats induced with phenobarbital or pregnenolone-16 alpha-carbonitrile. 4-MA (10 microM) had little or no effect on the oxidation of testosterone catalyzed by liver microsomes from mature male rats (which have low steroid 5 alpha-reductase activity). In contrast, the hydroxylated testosterone metabolites formed by liver microsomes from mature female rats (which have high steroid 5 alpha-reductase activity) accumulated to a much greater extent in the presence of 4-MA. Evidence is presented that 4-MA increases the accumulation of hydroxytestosterones by two mechanisms. First, 4-MA inhibited the 5 alpha-reduction of those metabolites (such as 6 beta-hydroxytestosterone) that were found to be excellent substrates for steroid 5 alpha-reductase. In the absence of 4-MA, these metabolites eventually disappeared from incubations containing liver microsomes from mature female rats. Second, 4-MA inhibited the formation of 5 alpha-dihydrotestosterone, which otherwise competed with testosterone for oxidation by cytochrome P-450. This second mechanism explains why 4-MA increased the accumulation of metabolites (such as 7 alpha-hydroxytestosterone) that were found to be poor substrates for steroid 5 alpha-reductase. Despite its marked effect on the accumulation of hydroxylated testosterone metabolites, 4-MA had no effect on their initial rate of formation by liver microsomes from either male or female rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Androstanes↗
PubMed1992

Glycinergic ligands modulate the rate of phosphorylation of the glycine receptor by protein kinase C.

The alpha subunit of the glycine receptor purified from rat spinal cord is rapidly and specifically phosphorylated by protein kinase C (Ruiz-Gómez et al., (1991) J. Biol. Chem. 266, 559-566). We report here that the rate of phosphorylation of the glycine receptor by this kinase is higher in the presence of agonists (glycine, beta-alanine) than in the presence of antagonists (strychnine, RU-5135). These results suggest that activated glycine receptors would be a preferential target for functional regulation through phosphorylation mechanisms.

Alanine↗
PubMed1984

gamma-Aminobutyric acid receptor binding antagonism by the amidine steroid RU5135.

The novel convulsant amidine steroid RU5135 inhibited gamma-aminobutyric acid receptor binding in membranes from seven regions of rat brain (IC50 = 11 +/- 2 nM against [3H]muscimol and 0.8 +/- 0.2 nM against [3H]bicuculline methochloride), apparently lowering the number of binding sites labeled with gamma-aminobutyric acid receptor agonists or antagonists. The steroid reversed the enhancement of benzodiazepine receptor binding by gamma-aminobutyric acid, pentobarbital, and etazolate, but did not inhibit the binding of the convulsant [35S]t-butyl bicylophosphorothionate. Thus, RU5135 shows very potent in vitro actions more resembling those of the gamma-aminobutyric acid site antagonist, bicuculline, than the chloride channel antagonist, picrotoxin.

Androstanes↗