Discovery of novel series of 6-benzyl substituted 4-aminocarbonyl-1,4-diazepane-2,5-diones as human chymase inhibitors using structure-based drug design.

A novel series of 6-benzyl substituted 4-aminocarbonyl-1,4-diazepane-2,5-diones were explored as human chymase inhibitors using structure-based drug design according to the X-ray cocrystal structure of chymase and compound 1. The optimization focused on the prime site led to the attainment of compounds that showed potent inhibitory activity, and among them, 18R shows a novel interaction mode.

Synthesis, cytotoxic activities and cell cycle arrest profiles of naphtho[2,1-α]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione glycosides.

Naphtho[2,1-α]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione (NPCD) is known to be a very potent and selective cyclin D1-CDK4 inhibitors and could induce strong G1 phase arrest in breast tumor cell lines. In this work, the synthesis of five NPCD glycosides and their cytotoxic activities against eight tumor cell lines are presented, as well as the investigation of their cell cycle arrest profiles. The results showed that the introduction of a sugar moiety onto NPCD did not affect much of their cytotoxic activities, while the subtle structure of the sugar moiety affected the underlying mechanism strongly. In addition, NPCD showed distinct cell-cycle arrest profiles in BxPC3 prostate cells and MCF-7 breast cells, while NPCD glycosides shared similar cell cycle arrest profiles in MCF-7 and BxPC3 cells, which also indicated that not only the indolocarbazole framework as well known before but the sugar moiety can have a profound impact on the mechanism of action for these types of compounds.

Inhibitory effects of opioids on compound action potentials in frog sciatic nerves and their chemical structures.

An opioid tramadol more effectively inhibits compound action potentials (CAPs) than its metabolite mono-O-demethyl-tramadol (M1). To address further this issue, we examined the effects of opioids (morphine, codeine, ethylmorphine and dihydrocodeine) and cocaine on CAPs by applying the air-gap method to the frog sciatic nerve. All of the opioids at concentrations less than 10 mM reduced the peak amplitude of the CAP in a reversible and dose-dependent manner. The sequence of the CAP peak amplitude reductions was ethylmorphine>codeine>dihydrocodeine> or = morphine; the effective concentration for half-maximal inhibition (IC(50)) of ethylmorphine was 4.6 mM. All of the CAP inhibitions by opioids were resistant to a non-specific opioid-receptor antagonist naloxone. The CAP peak amplitude reductions produced by morphine, codeine and ethylmorphine were related to their chemical structures in such that this extent enhanced with an increase in the number of -CH(2) in a benzene ring, as seen in the inhibitory actions of tramadol and M1. Cocaine reduced CAP peak amplitudes with an IC(50) value of 0.80 mM. It is concluded that opioids reduce CAP peak amplitudes in a manner being independent of opioid-receptor activation and with an efficacy being much less than that of cocaine. It is suggested that the substituted groups of -OH bound to the benzene ring of morphine, codeine and ethylmorphine as well as of tramadol and M1, the structures of which are quite different from those of the opioids, may play an important role in producing nerve conduction block.

[Study of cytotoxic and antiviral effects of some eye drops]. / Studiul proprietatilor citotoxice si antivirale ale unor colire.

The study of the cytotoxic and antiviral effect of six commercial mixtures, eye drops type, underlined the advantages of using eye drops with Indomethacin for Herpetic Keratitis, due to the antiviral effect and also for the lack of cytotoxicity.

Evidence for the presence of active cytochrome P450 systems in Schistosoma mansoni and Schistosoma haematobium adult worms.

Extracts of the adult worms of both Schistosoma mansoni and Schistosoma haematobium can metabolise some typical P450 substrates but to differing degrees. S. mansoni worm extracts displayed a approximately 12-fold higher specific activity for an aminopyrine substrate than rat liver microsomes. At 4 mM substrate concentration the demethylation reaction with N-nitrosodimethylamine (NDMA) (5 nmol HCHO/mg protein/min) was only half that of rat liver microsomes, whereas in extracts of S. haematobium, no detectable activity was found towards NDMA. Using ethylmorphine as substrate the demethylation activity of S. mansoni extracts (1.82 nmol HCHO/mg protein/min) was 5.5-fold lower than that of rat liver microsomes. Benzphetamine demethylase activity was also readily detectable in S. mansoni worm extracts at 6.79 nmol HCHO/mg protein/min compared with 10.20 nmol HCHO/mg protein/min in the case of rat liver microsomes. When aniline was used as substrate, surprisingly, no activity was found in worm extracts of either S. mansoni or S. haematobium, whereas rat liver microsomes showed high activity towards this amine. The anti-P450 2E1 and 2B1/2 cross-reacted with both worm homogenates and gave a specific band corresponding to a protein of molecular weight of approximately 50.0 kDa. A study with anti-P450 IVA antibody revealed that while this protein was strongly expressed in S. haematobium worm extracts, no immunoreactivity was observed with extracts of S. mansoni. Immunoblotting analyses with anti-P450 IIIA and P450 1A1 did not detect immunoreactive protein in either S. mansoni or S. haematobium.

[Effects of diclofenac sodium combined with dionine in cases with fibrinous membrane after intraocular lens implantation].

OBJECTIVE: The effects of diclofenac sodium(DFNa) combined with dionine in cases with fibrin exudation membrane on intraocular lens (IOL) were studied. METHODS: Thirty-two eyes, derived from sixteen adult pure bred New Zealand rabbits, were divided at random into two groups after extracapsular lens extraction with posterior chamber IOL implantation: (1) rabbits received DFNa eyedrops combined with dionine eyedrops; (2) rabbits received Pred forte eyedrops. The sum of fibrinous exudation membrane on IOL was observed on 1, 3, 5, 7, 14, 21, 30d postoperation. RESULTS: The fibrin exudations in the DFNa combined with dionine group is less than the pred forte group (P > 0.05). CONCLUSION: DFNa combined with dionine is effective in treating fibrin exudation membrane after extracapsular lens extraction and IOL implantation, and it is more effective than the pred forte.

[Experimental study on using diclofenac sodium or dionine topically to treat fibrinous membrane after intraocular lens implantation].

OBJECTIVE: To find a reasonable method for treating and preventing fibrinous membrane after intraocular lens (IOL) implantation by using diclofenac sodium or dionine topically. METHODS: Forty-eight eyes of twenty-four adult pure bred New Zealand rabbits were divided into three groups randomly. Group A: rabits received diclofenac sodium eyedrops; Group B: rabbits received dionine eyedrops; Group C: controlled. All the eyes received lens extraction combined with posterior chamber intraocular lens implantation. The fibrinous membrane was observed after 1, 3, 5, 7, 14, 21 and 30 days postoperatively. RESULTS: The fibrinous membran in Group A was less than that of Group B and Group C, (P < 0.05); the difference between group B and group C on fibrinous membrance was also statistically significant (P < 0.05). CONCLUSION: The study suggests that both diclofenac sodium and the dionine eyedrops can treat fibrinous membrane after IOL implantation. The effect of diclofenac sodium is better than that of dionine.

Evidence for a role of cytochrome P450 2D6 and 3A4 in ethylmorphine metabolism.

Ethylmorphine is metabolised by N-demethylation (to norethylmorphine) and by O-deethylation (to morphine). The O-deethylation reaction was previously shown in vivo to co-segregate with the O-demethylation of dextromethorphan indicating that ethylmorphine is a substrate of polymorphic cytochrome P450(CYP)2D6. To study further the features of ethylmorphine metabolism we investigated its N-demethylation and O-deethylation in human liver microsomes from eight extensive (EM) and one poor metaboliser (PM) of dextromethorphan. Whereas N-demethylation varied only two-fold there was a 4.3-fold variation in the O-deethylation of ethylmorphine, the lowest rate being observed in the PM. Quinidine, at a concentration of 1 microM, inhibited O-deethylation in microsomes from an EM, but was unable to do so in microsomes from the PM. The immunoidentified CYP2D6 and CYP3A4 correlated with the rates of O-deethylation (r = 0.972) and N-demethylation (r = 0.969), respectively. We conclude that the O-deethylation of ethylmorphine is catalysed by the CYP2D6 in human liver microsomes consistent with previous findings in healthy volunteers.

[The effect of phytin, benzonal and their combination administered prophylactically on the pharmacodynamics of drugs metabolized in the liver in hypokinesia]. / Vliianie fitina, benzonala i ikh kombinatsii pri profilakticheskom vvedenii na farmakodinamiku lekarstvennykh veshchestv, metaboliziruiushchikhsia v pecheni pri gipokinezii.

Hexenal, meprobamate, amidopyrine and ethylmorphine produced a significantly marked effect in animals under hypokinesia as compared with normal rats. When phytin, benzonal and their combination were used for preventive purposes, impaired pharmacodynamics of the tested drugs metabolizing in the liver disappeared. The investigations demonstrated that the preventive use of phytin in combination with benzonal is the most optimal in correcting the impairments of drug pharmacodynamics in hypokinesia.

[Characteristics of drug pharmacodynamics in irradiated rats]. / Osobennosti farmakodinamiki lekarstvennykh veshchestv u obluchennykh krys.

A whole-body exposure of rats to 8 Gy radiation is ineffective in 3 days, and in 6 days, it prolongs considerably the effect and increases the pharmacological activity of hexenal, meprobamate, ethylmorphine, and amidopyrine, inhibits the activity of amidopyrine demethylase, aniline hydroxylase, NADPH-cytochrome c reductase, and reduces the content of protein, cytochromes P-450 and b5 in a microsomal liver fraction.

Restoration of hydroperoxide-dependent lipid peroxidation by 3-methylcholanthrene induction of cytochrome P-448 in hepatoma microsomes.

Microsomal membranes from the slow-growing Morris hepatoma 9618A catalyze, in the presence of t-butyl hydroperoxide, lower rates of lipid peroxidation than rat liver microsomes. The cytochrome P-450 content of hepatoma microsomes is about 40% that of the liver. SKF 525-A, an inhibitor of mixed-function oxidase, produces in hepatoma microsomes a P-450 type I binding spectrum similar to that of hepatic microsomes. The concentration of the inhibitor required for half-maximal spectral change is about 2 microM in both microsome types. SKF 525-A or ethylmorphine inhibit lipid peroxidation of normal and tumor microsomes to the same extent (about 60%). Treatment of the tumor-bearing rats with 3-methylcholanthrene increases the hepatoma cytochrome P-450 to values comparable to those of control membranes, although the hemoprotein has a peak in the CO-reduced difference absorption spectrum at 448 nm. The cytochrome P-448 induction is accompanied by an almost complete restoration of the hydroperoxide-dependent lipid peroxidation.

On the mechanisms of glutathione depletion in hepatocytes exposed to morphine and ethylmorphine.

Incubation of isolated rat hepatocytes with either morphine or ethylmorphine resulted in glutathione (GSH) depletion followed by loss of cell viability. Pretreatment of cells with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to inactivate glutathione reductase did not markedly affect the rates of GSH depletion seen in untreated cells. In contrast, hexobarbital stimulated H2O2 production in isolated liver microsomes, incubated aerobically with NADPH, whereas the effects of morphine and ethylmorphine on microsomal H2O2 production were minimal. Finally, incubation of hepatocytes with radioactively labeled morphine resulted in formation of 2 glutathione conjugates, one of which was tentatively identified as formyl glutathione. We conclude that GSH consumption during the metabolism of morphine or ethylmorphine by hepatocytes is due mainly to formation of glutathione conjugates.

Effect of benzopyrone derivatives on drug activity and metabolism.

In female rats, zoxazolamine paralysis time and mortality caused by indomethacin were significantly reduced by pretreatment with khellin, 7,8-benzoflavone or rutin. Pretreatment with khellin and 7,8-benzoflavone increased the in vitro zoxazolamine and ethylmorphine metabolism. These results were compared with those obtained by equimolar doses of phenobarbital, pregnenolone-16 alpha-carbonitrile and spironolactone in experiments performed simultaneously. It was concluded: Khellin, 7,8-benzoflavone and rutin increased the body's resistance to drugs via induction of the drug metabolizing enzymes of the liver, this action has about the same magnitude with that of phenobarbital and pregnenolone-16 alpha-carbonitrile. For the benzopyrone derivatives, some common structural features have been indicated as probable structural requirements for drug metabolizing enzyme inductive activity in this group of compounds.

The inhibition of bacterial bioluminescence by xenobiotics.

The effect of various xenobiotic substrates of microsomal cytochrome P-450, including dimethylaniline, ethylmorphine, hexabarbital and aminopyrine, on the bioluminescence of the bacteria Vibrio fischeri and the bacterial luciferase mixed-function oxidase system is described. These compounds are effective inhibitors of the luminescence reaction. The inhibition provided evidence for the competitive nature of the interactions between xenobiotics and an aliphatic aldehyde, which is a substrate of bacterial luciferase, at the binding site for cytochrome P-450. The bioluminescence method is suitable for the analysis of metabolism and detoxication of various xenobiotics.