Novel inhibitors of 5α-reductase

5α-reductase inhibitors represent a new pharmacological treatment either for very severe diseases, such as benign prostatic hyperplasia (BPH) and prostatic cancer or for skin disorders, such as acne, male pattern baldness and hirsutism.     

α-Adrenoceptor activity of arylalkylimidazoles is improved byα-methylation and impaired byα-hydroxylation

Summary To investigate the effects of hydroxyl and methyl substitution of the alkyl bridge bond on the-adrenoceptor activity of arylalkylimidazole derivatives, the cardiovascular effects of the molecules were studied in anaesthetized and pithed rats. The compounds studied were 4(5)-substituted imidazole derivatives with a methano, ethano or etheno bridge between the imidazole and the 2-, 2,3- or 2,6-methyl substituted phenyl rings. The hypotensive and bradycardic activities of the molecules in the anaesthetized rat were always reduced by-hydroxylation and usually augmented by-methylation of the bridge between the imidazole and phenyl rings. Hydroxylation was associated with a consistent, marked decrease in vasopressor and sympatho-inhibitory activity in the cardiovascular system of the pithed rat, but a methyl moiety as a bulky substituent in the-position of the alkyl bridge did not decrease but even caused an increase in-adrenoceptor activity in this test system. The detrimental effect of-hydroxylation of the compounds at ₁- and ₂-adrenoceptors supports the notion that the interaction of the imidazoles at-adrenoceptor is different from that of the classical, noradrenaline-like phenethylamines. The results also suggest that the alkyl bridge between the phenyl and imidazole rings of the imidazoles may contribute directly to the binding process.     

Proteolytic maturation of transforming growth factor-α

Summary Transforming growth factor- (TGF-) is a mitogenic peptide hormone produced extracellularly, by tumor cells, and by virally and chemically transformed cells in culture. TGF- is almost certainly derived from its precursor protein (pro-TGF-) by limited endoproteolysis, but physiologically relevant processing enzyme(s) of the pro-TGF- protein and the cellular or subcellular compartment in which processing takes place are not known with certainty. We previously detailed [Cappelluti, E. and Harris, R.B., Biochemistry, 32 (1993) 551] the discovery, characterization and purification of novel, elastase-like enzymes (molecular weight 38 000) from oncogenically transformed rat liver epithelial cells or cultural Schwann cells transfected with SV40-large T antigen. The elastase-like enzyme appeared to be specifically induced in the transformed epithelial cells compared with the level of enzyme in the nontransformed parental cells. In the intervening time, other elastase-like serine proteinases have been implicated in processing pro-TGF- in other human carcinoma cell lines. We now report that the elastase-like enzymes, purified from transformed Schwann or liver epithelial cells, are inhibited in a time- and concentration-dependent fashion with three differently substituted monocyclic -lactam-based compounds originally developed as specific inhibitors of polymorphonuclear leukocyte elastase, thus further supporting the elastase-like character of the putative pro-TGF- processing enzymes. We also report the presence of the elastase-like enzyme in two different human malignant mammary cell lines, but even though MCF-7 cells receiving high doses of radiation in vitro show an increased level of expression of TGF-, the elastase-like enzyme does not appear to be induced in these cells following irradiation.     

Characterization of the self-association of human interferon-α2b, albinterferon-α2b, and pegasys

The self-association of human interferon-α2b (hIFN-α2b), albinterferon-α2b (a recombinant protein with human serum albumin and hIFN-α2b peptides fused together in a single polypeptide chain), and Pegasys (PEGylated hIFN-α2a) was characterized by analytical ultracentrifugation analyses. By examining the apparent sedimentation coefficient distribution profiles of each protein at different concentrations, it was concluded that the above three proteins are self-associating in albinterferon-α2b formulation buffer. By model fitting of sedimentation data using SEDANAL software, the stoichiometry and equilibrium constants of the self-association of these proteins were characterized. The self-association of hIFN-α2b results in the formation of stable dimers, fast-reversible tetramers, octamers, and hexadecamers. In contrast, although both albinterferon-α2b and Pegasys are self-associated, their self-association stoichiometries are significantly different from that of hIFN-α2b. The self-association of albinterferon-α2b results in the formation of reversible dimers and trimers, whereas the self-association of Pegasys gives only reversible dimers. The self-association behaviors of hIFN-α2b and albinterferon-α2b involves attractive electrostatic forces, which can be suppressed to a negligible level in low pH (pH 4.0-4.5) and high salt concentration (400 mM NaCl) buffer, allowing quantification of their size variant contents by sedimentation velocity analysis.     

α2-adrenoceptor regulation of blood glucose homeostasis

The α(2A)-adrenoceptor has been identified as an important regulator of blood glucose homeostasis. α(2A)-Adrenoceptors on pancreatic β-cells inhibit insulin secretion, and α(2A)-adrenoceptors on sympathetic nerves and on adrenomedullary chromaffin cells limit sympathoadrenal output. Recently, human α(2A)-adrenoceptor gene polymorphisms that influence α(2A)-adrenoceptor expression and function have been described. Increased α(2A)-adrenoceptor expression has been associated with impaired glucose-stimulated insulin secretion, elevated fasting blood glucose levels and an increased risk of type 2 diabetes. Accordingly, administration of α(2)-adrenoceptor agonists generally increases blood glucose levels, in spite of the ensuing sympatholysis that would be expected to lower blood glucose as a result of diminished α(1)- and β-adrenoceptor activation. α(2)-Adrenoceptor antagonists increase insulin secretion and reduce blood glucose levels by inhibiting tonically active α(2A)-adrenoceptors on pancreatic β-cells, but may also enhance sympathoadrenal output. In addition, α(2)-adrenoceptor antagonists potentiate the insulinotropic effect of sulphonylurea drugs, pointing to a potentially serious adverse drug interaction when the two classes of drugs are combined. The α(2)-adrenoceptor antagonist atipamezole is widely used in veterinary medicine, and sulphonylureas are prescribed for the treatment of type 2 diabetes in cats and dogs. Even if no dedicated α(2)-adrenoceptor antagonists are in clinical use in humans, some antipsychotic and antidepressant drugs are relatively potent α(2)-adrenoceptor antagonists. In the treatment of type 2 diabetes, α(2)-adrenoceptor agonists could possibly protect against sulphonylurea-induced hypoglycaemia, and α(2)-adrenoceptor antagonist drugs could improve insulin secretion. The potential usefulness of such drugs may vary between individuals, depending on α(2A)-adrenoceptor genetics, sympathetic tone and concomitant pathological conditions, such as cardiovascular disease and obesity.     

Preparation and use of N-acetyl-α-amino acids

N-acetyl derivatives of L-glutamine, L-proline, and 4-hydroxy-L-proline were synthesized in aqueous solutions with acetic anhydride as the acetylating agent. The resulting compounds were used as medicinal substances.     

Computational models for 5αR inhibitors for treatment of prostate cancer: review of previous works and screening of natural inhibitors of 5αR2

Taking into consideration the high importance of the drug target 5-α-reductase (5αR) in prostate cancer in this work we are going first to review previous works and discuss works related to the computer aided drug design of 5αR inhibitors. We report new results in the in silico screening of natural 5αR inhibitors. Traditionally, drugs were discovered by testing compounds synthesized in time consuming multi-step processes against a battery of in vivo biological screens. Promising compounds were then further studied in development, where their pharmacokinetic properties, metabolism and potential toxicity were investigated. Here we present a study on herbal lead compounds and their potential binding affinity to the effectors molecules of major disease like Prostate Cancer. Clinical studies demonstrate a positive correlation between the extent of 5αR type 2 (5αR2) and malignant progression of precancerous lesions in prostate. Therefore, identification of effective, well-tolerated 5αR inhibitors represents a rational chemo preventive strategy. This study has investigated the effects of naturally occurring non-protein compounds berberine and monocaffeyltartaric acid that inhibits 5αR type2. Our results reveal that these compounds use less energy to bind to 5αR and inhibit its activity. Their high ligand binding affinity to 5αR introduce the prospect for their use in chemopreventive applications; in addition they are freely available natural compounds that can be safely used to prevent prostate cancer.     

Cost-effectiveness of TNF-α-blocking agents in the treatment of rheumatoid arthritis

The current literature covering cost-effectiveness and cost-utility analyses of biological treatments in patients with rheumatoid arthritis (RA) are reviewed in order to discuss options and limitations for future application of these highly priced drugs in routine clinical practice. The cost-effectiveness and cost-utility ratios of the studies analysed are converted into the corresponding Euros of the publication year. Etanercept treatment achieved a cost-effectiveness ratio of €44,300 (2002)/ACR 20 (20% response according to American College of Rheumatology criteria) and €43,100 (2002)/ACR 70WR (ACR 70 weighted response) compared with sulfasalazine and methotrexate, respectively, in methotrexate-naive RA. In methotrexate-resistant RA, the combination of etanercept and methotrexate is compared to a combination therapy of methotrexate, sulfasalazine and hydroxychloroquine revealing costs of €46,100 (2000)/ACR 20, and €37,700/ACR 70WR. The cost-utility ratios for infliximab treatment range from €16,000 to almost 166,000/QALY (quality adjusted life-year) gained, the studies investigating etanercept treatment show a ratio of ～ €25,000 and 120,000/QALY gained. No substantial differences of cost-utilities of infliximab and etanercept were found. The administration of these drugs as third-line therapy is regarded cost-effective compared to other well-accepted therapies with comparable cost-utility ratios of < €50,000/QALY gained. Still, data on economic outcomes of RA trials are sparse and further cost-effectiveness and cost-utility evaluations are needed.     

Pharmacokinetic investigations in man of two acetyl derivatives of 16α-gitoxin

Summary ³H-16-acetyl-16-gitoxin or³H-pentacetyl-16-gitoxin were injected iv or administered po to 15 volunteers and 3 patients. The elimination half-life and excretion in urine within 4 days were estimated as a percentage of the administered radioactivity, and metabolic studies on the fate of the administered glycosides were performed. In volunteers the following results were obtained:³H-16-acetyl-16-gitoxin 1 mg iv.: 50±11 h, 28.3±4.1%;³H-16-acetyl-16-gitoxin 1mg po: 48±8 h, 25.4±2.8%;³H-penta-acetyl-16-gitoxin 2 mg po: 51±12 h, 20.7±3.2%, respectively. In 3 patients with a cannulated bile duct 9.9% (mean) of the administered³H-16-acetyl-16-gitoxin was excreted. By comparison of the radioactivity excreted in urine following the 2 routes of 16-acetate administration, the percentage absorption was calculated to be 88.5%. In serum and urine 16-acetyl-16-gitoxin and 16-gitoxin were found as possible metabolites of both glycosides, in the ratio of 75–85: 15–25, and both metabolites were also found in bile. Within 16 h after penta-acetate administration, two additional metabolites (bis-acetylderivatives of 16-gitoxin) were detected in serum and urine within 16 h after administration of pentaacetate.     

Hydroxylation of 16α-methyl-17α,21-dihydroxypregn-4-en-3-one

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 24, No. 6, pp. 56–58, June, 1990.     

α1-adrenoceptor subtype affinities of drugs for the treatment of prostatic hypertrophy

Summary We have used radioligand binding and inositol phosphate accumulation studies to determine the affinity at mixed _1A- and _1B-adrenoceptors (rat cerebral cortex and kidney), _1A-adrenoceptors (rat cerebral cortex and kidney following inactivation of _1B-adrenoceptors by chloroethylclonidine treatment) and _1B-adrenoceptors (rat spleen) for drugs currently under investigation for the treatment of benign prostatic hypertrophy, alfuzosin, naftopidil and (–)- and (+)-tamsulosin. Alfuzosin and naftopidil had similar affinities in all model systems (approximately 10 nM and 130 nM, respectively) and lacked relevant selectivity for ₁-adrenoceptor subtypes. Their potency to inhibit noradrenaline-stimulated inositol phosphate formation in cerebral cortex matched their affinities as determined in the binding studies. Tamsulosin had higher affinity at _1A- than at _1B-adrenoceptors, and was slightly more potent than alfuzosin and naftopidil at _1B- and considerably more potent at _1A-adrenoceptors. However, the interaction of the tamsulosin isomers with chloroethylclonidine-insensitive (_1A-like) adrenoceptors was complex. A detailed analysis of the tamsulosin data and those obtained with other drugs, most notably noradrenaline and oxymetazoline, suggested that chloroethylclonidine-insensitive ₁-adrenoceptors may be heterogenous and that this heterogeneity may differ between cerebral cortex and kidney of the rat.     

Isolation of isomaltol-α-d-glucopyranoside1 and ketopropyl-α-d-glucopyranoside2 from Korean red ginseng

Based on spectral and chemical evidences, two glycosides isolated from Korean red ginseng are characterized as isomaltol-α-d-glucopyranoside and ketopropyl-α-d-glucopyranoside. These compounds are not found in Korean white ginseng.     

Adenosinergic modulation of 3α-hydroxy-5α-pregnan-20-one induced catalepsy in mice

  Rationale: Neurosteroid 3α, 5α THP, a positive allosteric modulator of the GABA_A receptor Cl^– ionophore complex, induces catalepsy-like dopamine antagonists, adenosine agonists or GABA agonists. Adenosine and dopamine receptors are co-localized on GABAergic neurons in the striatum and regulate GABA-mediated neurotransmission. Moreover, the antagonistic interactions between specific subtypes of adenosine and dopamine receptors are involved in motor depressant or motor stimulant effects of adenosine receptor agonists or antagonists, respectively. Such interaction may modulate neurosteroid-induced catalepsy. Objective: This study examined the modulation of 3α, 5α THP-induced catalepsy by adenosinergic agents. Methods: Catalepsy induced by 3α, 5α THP (2–8 μg, ICV) was assessed by bar test periodically up to 3 h in mice. Adenosine A₁, A_2A or A₃ receptor agonists or antagonists were given IP or ICV prior to 3α, 5α THP. Some animals received IP dopamine D₂ receptor agonist or antagonist 30 min prior to above combination treatment. Results: Adenosine A₁, A_2A, and A₃ receptor agonists potentiated, whereas adenosine A_2A receptor antagonists, but not A₁ antagonists, reversed 3α, 5α THP-induced catalepsy. These effects of adenosine agonists and antagonists were abolished by prior administration of bromocriptine, the dopamine D₂ receptor agonist and spiperone, the dopamine D₂ receptor antagonist, respectively. Conclusions: These findings suggest specific adenosine-dopamine receptor interaction in the striatum to modulate 3α, 5α THP-induced catalepsy. Received: 1 November 1998 / Final version: 5 January 1999     

Synthesis and Biological Activities of 5-Thio-α-GalCers

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Microbial 9α-hydroxylase: Epoxidation of 9(11)-dehydro-17α-methyl-testosterone

Steroid 9alpha-hydroxylase is a key enzyme system in steroid nucleus degradation in company with Delta(1)-dehydrogenase. To examine 9alpha-hydroxylase activity during microbial transformation of steroids, 9(11)-dehydro-17alpha-methyl-testosterone was adopted as a stable substrate for preventing the rupture of steroid nucleus. UsingNocardia restrictus ATCC 14887 capable of introducing a 9alpha-hydroxyl group into steroids, 9alpha, 11alpha-oxido-17beta-hydroxy-17alpha-methyl-4-androstene-3-one and 9alpha, 11alpha-oxido-17beta-hydroxy-17alpha-methyl-1, 4-androstadiene-3-one were obtained. These microbiologically transformed products could be used as reference compounds in the enzyme assay.     

Purification of the NADH reductase component of the steroid 9α-hydroxylase fromMycobacterium fortuitum

The NADH reductase component of the steroid 9α-hydroxylase fromMycobacterium fortuitum was purified to homogeneity. Recovery of the enzyme from the 50≈60% ammonium sulfate saturated fraction was 49%, with a purification factor of 100-fold. The NADH reductase has a relative molecular mass of 60 KDa as determined by SDS-PAGE. The absorption maxima at 410 and 450 nm indicate the presence of iron-sulfur group and flavin. These prosthetic groups seemed to function as redox groups that transfer electrons from NADH to the following protein. The K_M value for NADH as substrate was 68 μM. The NH₂-terminal amino acid sequence of the reductase was determined as Met-Asp-Ala-Ile-Thr-Asn-Val-Pro-Leu-Pro-Ala-Asn-Glu-Pro-Val-His-Asp-Tyr-Ala-Thr. This sequence does not show a homology with the NH₂-terminal sequences reported for the reductase component of other monooxygenases, suggesting that the NADH reductase component of the steroid 9α-hydroxylase system is novel.