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At least 127 records · Page 7Linked to original sources
PubMed2005

Beneficial effects of a new 20-hydroxyeicosatetraenoic acid synthesis inhibitor, TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide], on hemorrhagic and ischemic stroke.

The present study characterized the effects of TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide], a new selective inhibitor of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), on the metabolism of arachidonic acid by human and rat renal microsomes and the inhibitory effects of this compound on hepatic cytochrome P450 enzymes involved in drug metabolism. The effects of TS-011 on the fall in cerebral blood flow following subarachnoid hemorrhage (SAH) and in reducing infarct size in ischemic stroke models were also examined since 20-HETE may contribute to the development of cerebral vasospasm. TS-011 inhibited the synthesis of 20-HETE by human renal microsomes and recombinant CYP4A11 and 4F2, 4F3A, and 4F3B enzymes with IC50 values around 10 to 50 nM. It had no effect on the activities of CYP1A, 2C9, 2C19, 2D6, or 3A4 enzymes. TS-011 inhibited the synthesis of 20-HETE by rat renal microsomes with an IC50 of 9.19 nM, and it had no effect on epoxygenase activity at a concentration of 100 microM. TS-011 (0.01-1 mg/kg i.v.) reversed the fall in cerebral blood flow and the increase in 20-HETE levels in the cerebrospinal fluid of rats after SAH. TS-011 also reduced the infarct volume by 35% following transient ischemic stroke and in intracerebral hemorrhage in rats. Injection of 20-HETE (8 or 12 mg/kg) into the carotid artery produced an infarct similar to that seen in the ischemic stroke model. These studies indicate that blockade of the synthesis of 20-HETE with TS-011 opposes cerebral vasospasm following SAH and reduces infarct size in ischemic models of stroke.

Animals↗
PubMed1997

Efficacies of two novel azole derivatives each containing a morpholine ring, UR-9746 and UR-9751, against systemic murine coccidioidomycosis.

UR-9746 and UR-9751 are novel azole derivatives each containing a morpholine ring. They were examined for both in vitro and in vivo activities against Coccidioides immitis. In vitro, UR-9746 and UR-9751 were active, with MICs of 25 and 3.1 micrograms/ml, respectively, against C. immitis Silveira; minimum fungicidal concentrations were > 100 micrograms/ml, the highest concentration tested, for both compounds. Antifungal activity in serum showed the desirable characteristic of remaining severalfold above the MIC at all times. Against systemic murine coccidioidomycosis, UR-9746 and UR-9751 prolonged survival at dosages of > or = 10 mg/kg/day and showed increased reduction of infectious burden in the spleens, livers, and lungs of treated mice with escalating dosage. Both compounds lacked observable toxicity and on a milligram-per-kilogram of body weight basis were > or = 10-fold superior to fluconazole in prolonging survival and clearing infection with C. immitis.

Animals↗
PubMed1988

Isolation and identification of a morpholine-degrading bacterium.

A gram-positive, slowly growing rod effectively utilizing morpholine as the sole source of organic carbon, nitrogen, and energy was isolated from a mixed culture in a laboratory reactor. The strain was tentatively identified as Mycobacterium aurum. Its growth characteristics at 20 degrees C and pH 6.5 were as follows: maximum specific growth rate, 0.052 h-1; half-velocity constant, 1.3 mg/liter; and yield, 0.37 g/g. The optimum temperature and pH were 31 degrees C and 6.0, respectively.

Biodegradation, Environmental↗
PubMedDate not supplied

Interactions of novel morpholine and hexamethylene derivatives of anthracycline antibiotics with DNA.

Doxorubicin (DOX), daunorubicin (DRB), epidoxorubicin (EDOX) and their analogues with a 3'-NH2 group in daunosamine form a covalent bond with a 2-NH2 group of guanine via a methylene group from formaldehyde (CH2O). It is assumed that a Schiff base type intermediate is formed between CH2O and the 3'-NH2 group in the reaction. This reaction is supposed to occur in the cell. New analogues of anthracyclines with formamidine functionality bound to C-3' of daunosamine and containing the bulky morpholine (DRBM, DOXM and EDOXM) or hexamethyleneimine rings attached are studied in our laboratory. These substituents decrease the association of the drugs to DNA and potentially hinder the formation of Schiff base-intermediates. Our experiments indicate that the formation of the covalent complexes by DRB, DOX and EDOX under these conditions is confirmed by a high enhancement (17-40x) of the inhibition of overall RNA synthesis by E. coli RNA polymerase on T7 DNA. DRBM and DOXM exhibit a lower enhancement of the inhibition by CH2O (7-13x). The other analogues show a 1.6-3x increase of inhibition. Hence, their covalent binding is lower than that of the parent compounds. These conclusions are confirmed by spectrophotometric estimations following removal of non-covalently associated drugs. Electrophoretic analysis of drug-DNA complexes formed in the presence of CH2O indicates that DRBM and DOXM as their parent compounds induce labile cross-links in DNA. Comparison of the results obtained at the subcellular level with cytotoxicity estimations indicates that there is a correlation between cytotoxicity of the anthracyclines on L1210 cells and transcriptional template activity of drug-DNA complexes formed in the presence of CH2O (r = 0.64; n = 9). These data confirm a notion that covalent attachment of anthracyclines to DNA is an essential event leading to cytotoxicity.

Anthracyclines↗
PubMed1976

The relationship between chemical structure and basicity in some morpholine compounds.

The influence of various substituents upon the pKa values of a series of 2-phenylmorpholines is discussed. The results are interpreted in terms of the preferred conformations of the morpholine ring and the inductive effect of the various substituents. The lack of analgesic activity in these compounds could be attributed to their low pKa.

Analgesia↗
PubMed2003

[Antithrombotic effects of morpholine and piperazine ring derivatives and their molecular mechanism].

AIM: To investigate the antithrombotic effects of morpholine and piperazine ring derivatives and their mechanisms. METHODS: In isolated rat aorta-precontracted with norepinephrine (NE), the vasodilatory effects of compounds with novel structure were investigated. Mice was given kappa-carrageenin i.p. and kept at the temperature of (20-21) degree C. RESULTS AND CONCLUSION: Active candidate compounds including MOPMC, 2FBMPC, MPTMBC, DMHPPP and PPVP were shown to antagonize thrombosis at the dose of 1 mg.kg-1 through activating the endothelial target for acetylcholine; while the contrasting compounds MAPC, 4C3FBMOC, mTBMPC, MONVP and MPNVP showed no significant effect on the tension of isolated aorta strips or significant antithrombotic effects at the same dose. The antithrombotic mechanism of novel compounds is not relevant to hemostatic systems or functions of platelet aggregation directly, but they can promote endothelial cells to release tissue-type plasminogen activator (t-PA) and inhibit the activity of plasminogen activator inhibitor-1 (PAI-1).

Animals↗
PubMedDate not supplied

[Research concerning rutin semisynthetic derivatives, synthesis and pharmaco-toxicological properties of some new morpholine and piperidine derivatives].

In order to continue the research of the rutin semisynthetic derivatives we obtained some new morpholine and piperidine derivatives. Melting points, solubility, yield, C, H, N elemental analysis and UV spectra characterised all of these compounds. The toxicity was established by intraperitoneal administration at mice; the values of LD50 are between 743.75 and 856.25 mg/kg (medium toxicity). Pharmacological assays included the following parameters: leukocytes formula, NBT test, and serum complement activity. The new derivatives of rutin have a very good solubility in water, a pH closed to physiological value and immunosuppressive activity: peripheric blood PMN and lymphocytes are decreased; fagocytic capacity of peripheric blood PMN is also decreased; serum complement activity is not changed.

Animals↗
PubMed2005

[Spectroscopic research on the interaction of 2-(4-dimethylaminophenyl)-5-fluoro-6-(morpholin-4-yl)-1H-benzimidazole and calf thymus DNA].

UV-Vis spectra of the aqueous solutions of 2-(4-dimethylaminophenyl)-5-fluoro-6-(morpholin-4-yl)-1H-benzimidazole (1) at different pH values revealed that compound 1 is a tertiary base, which can combine three protons. Through the non-linear least square method, the logarithm of the three accumulative protonation constants of compound 1, namely, lgbeta1, lgbeta2 and lgbeta3, were determined to be 4.96 +/- 0.03, 5.72 +/- 0.07 and 7.95 +/- 0.10, respectively. UV-Vis and the steady-state fluorescence spectra indicated that a special interaction occurs between compound 1 and calf thymus DNA at the pH value of 3.40, of which thebinding constant, Kb, is (2.30 +/- 0.10) x 10(4) mol(-1) x L. Compound 1 in the concentration range of 10(-8) to 1.2 x 10(-6) mol x L(-1) has a potential application to the quantitative determination of DNA.

Animals↗
PubMed1991

[In vitro antifungal activity of amorolfine, a new morpholine antimycotic agent].

In vitro antifungal activities of amorolfine (MT-861), a newly developed morpholine antimycotic agent, against a wide range of pathogenic fungal strains were investigated using an agar-dilution method with an imidazole antifungal agent, clotrimazole (CTZ), as the reference drug. The results showed that MT-861 had a broad antifungal spectrum, and was active against all of the pathogenic fungi tested except nonpigmented filamentous fungi such as aspergilli and penicillia. Dermatophytes and Malassezia furfur was the most highly susceptible to MT-861. Antifungal activities of MT-861 against most strains of these fungi as well as those against most strains of dimorphic fungi were higher than those of CTZ. By contrast, MT-861 showed lower activities against pathogenic yeasts such as Candida albicans than CTZ. Several assay conditions, such as inoculum size of fungi, incubation time, media pH and compositions including serum supplementation, affected MT-861 activities against C. albicans and, to lesser extents, those against Trichophyton mentagrophytes. MIC values of MT-861 against C. albicans and other Candida spp., were the lowest on casitone agar. MT-861 exerted fungicidal actions toward susceptible fungi such as T. mentagrophytes and Sporothrix schenckii at relatively low concentrations, and these activities were increased when the time of incubation was extended beyond 24 hours after inoculation of testing organisms. Susceptibilities of any strains of C. albicans and C. glabrata to MT-861 were not reduced by as many as 15 successive transfers in MT-861 containing media.

Antifungal Agents↗
PubMed1990

[Purging of leukemic cells from mouse marrow and tumor suspensions with lysosomotropic agent N-dodecyl morpholine].

The lysosomotropic agent N-dodecyl morpholine (NDM) showed a marked killing of mice leukemic cells in vitro: 100% killing of L7811 leukemic cells (10(6) cells/ml) at a concentration of 15 micrograms/ml. Bone marrow of 615 mice containing 5% L7811 leukemic cells was treated with NDM and then infused into normal 615 mice. Mean survival times (MST) were 16.3 +/- 1.78 days and 15.8 +/- 2.32 days for control group and solvent group respectively, while the MST of groups treated with NDM were more than 40 days. When the marrow was infused into lethally irradiated mice, those mice receiving NDM-purged marrow died of radiation disease instead of leukemia. But when the number of marrow cells infused was increased to 2 x 10(6) cells/mouse, the mice survived for significantly longer times than did control group mice or those of the group infused with 10(6) cells/mouse.

Animals↗
PubMedDate not supplied

Colorimetric determination of certain phenothiazine drugs by using morpholine and iodine-potassium iodide reagents.

A colorimetric method was developed for the quantitative estimation of 11 phenothiazine drugs. The method is based on the interaction of unsulfoxidized drug with morpholine and iodine-potassium iodide reagents. The interaction for all studied phenothiazine drugs yields a blue product with 2 absorption maxima: one in the range of 620-640 nm with lower molar absorptivity and the other in the range of 662-690 nm with higher molar absorptivity. The color was stable for at least 10 h. The reproducibility and recovery of the method were excellent. The method was applied successfully to the analysis of various commercially available phenothiazines in different dosage forms. The results were comparable to those obtained by official procedures. The suitability of the method for detection and estimation of promethazine excreted in urine has been suggested by preliminary experiments. Reaction products have been isolated and identified.

Antipsychotic Agents↗
PubMedDate not supplied

Colorimetric determination of C-2 unsubstituted phenothiazines, using morpholine and N-bromosuccinimide.

A colorimetric method for quantitative determination of 6 C-2 unsubstituted phenothiazine derivatives is described. The method is based on reaction of phenothiazine derivative with morpholine and N-bromosuccinimide reagents in aqueous methanol at 60 degrees C to produce a blue color. Beer's law is obeyed in a wide range of concentrations for all 6 compounds at 660 nm. Optimum analytical conditions were determined and the produced color is stable for at least 24 h. Analytical data for determination of the pure compounds are presented together with the application of the proposed method to analysis of some pharmaceutical preparations. The results compare favorably with those of official methods. Furthermore, the method is specific for intact drug in the presence of oxidative decomposition products. The reaction product has been isolated and identified and a possible reaction mechanism is suggested.

Antipsychotic Agents↗
PubMed1988

Lack of differential sensitivity of normal hematopoietic stem cells and murine lymphoblastic leukemic cells to a lysosomotropic agent, N-dodecyl morpholine.

The effect of N-dodecyl morpholine (NDM), a lysosomotropic compound, on the clonogenic capacity of GK15, Sp2.0, Hb131, and L1210 lymphoblastic tumor cells and CFU-GM and CFU-S progenitor cells from DBA/2 mice was measured in order to evaluate the potential use of this compound for the purging of tumor-contaminated bone marrow (BM) in autologous BM transplantation. The growth of clonogenic tumor cells from all of the tested cell lines was inhibited with doses of NDM that also killed 100% CFU-GM and CFU-S, and no optimal dose could be found in this animal model to purge marrow while sparing sufficient stem cells to ensure engraftment in syngeneic BM transplantation.

Animals↗
PubMed1988

Effect of teomorfolin [N-(7'-theophylline acetyl)morpholine], a new drug, on dislipidaemic conditions induced in the rat.

A study of a new compound with an original structure, teomorfolin [N-(7'-theophylline acetyl)morpholine], was performed in the rat to investigate interaction with experimentally induced dislipidaemic disturbance related to atherosclerotic disorders. The drug succeeded in normalizing the cholesterol and triglyceride serum levels in acute as well as in chronic hyperlipaemia, and, in this connection, it provoked a significant increase of serum alpha-lipoproteins and a decrease of serum beta-lipoproteins, with a consequent improvement of the beta/alpha ratio. In addition, it significantly limited the lipolytic effect produced by adrenaline. Moreover, the drug demonstrated in vitro and in vivo platelet anti-aggregant activity and was able to increase erythrocyte flexibility. Finally, the drug inhibited prostacyclin biosynthesis; this action could explain the anti-aggregant activity demonstrated by teomorfolin. In conclusion, the chemical under investigation showed a wide spectrum of biological properties that interfere with metabolic disturbances involved in atherosclerotic conditions.

Adenosine Diphosphate↗
PubMed1979

Pharmacological and biochemical studies on a new compound, 2-(7-indeyloxymethyl)morpholine hydrochloride (YM-08054-1), and its derivatives with potential antidepressant properties.

Antidepressant properties of a new indene derivative, YM-08054-1, and its related compounds were compared with those of tricyclic antidepressants and viloxazine. The potencies of YM-08054-1 to inhibit uptake of both 14C-norepinephrine (14C-NE) and 14C-5-hydroxytryptamine (14C-5-HT) by the rat brain synaptosomes were similar to those of amitriptyline and imipramine. Other indene derivatives with an N-alkylated morpholine ring were proved to have less effect on the uptake of either 5-HT or NE than was YM-08054-1. YM-08054-1 was the most potent among all of the tested antidepressants in the inhibition of reserpine-induced facilitation of convulsions as well as in the potentiation of reserpine-induced facilitation of convulsions as well as in the potentiation of 5-hydroxytryptophan (5-HTP)-induced syndromes in mice, though the inhibitory effect of this agent on reserpine-induced hypothermia was weaker than that of either amitriptyline or desipramine, suggesting relatively selective effects of YM-08054-1 upon 5-HT rather than NE uptake in vivo. Neither viloxazine nor iprindole potentiated the responses to 5-HTP. YM-08054-1 was devoid of peripheral anticholinergic activity and exhibited weak local anesthetic effect as well as low acute toxicity when compared with amitriptyline. The results indicate that YM-08054-1 has a novel profile as an antidepressant agent which is quite different from that of either viloxazine or tricyclic compounds.

Anesthetics, Local↗
PubMed1983

Effect of two graded doses of whole-body X-irradiation and radioprotection by the use of S-phenethyl formamidino 4(N-ethyl isothioamide) morpholine dihydrochloride.

The protection offered by a newly synthesized compound (S-phenethyl-formamidino-4(N-ethyl isothioamide) morpholine dihydrochloride) against radiation effects on DNA, RNA and protein biosynthetic processes in the brain, and on metabolites of 5-HT and nor-adrenalin, i.e., 5-HIAA and VMA, in the urine, including the radiobiological damage to thyroid and testes, was evaluated. The use of the compound prior to irradiation prevented radiation-induced changes in the thyroid and testes. The radiation-induced alterations in the pattern of DNA, RNA, protein in the brain, and in 5-HIAA and VMA in urine could be averted by treatment with this compound prior to each dose of X-irradiation.

Animals↗
PubMed1984

Studies on the release of solubilized drugs from ointment bases. Part 8: The effect of emulsifiers on pharmaceutical availability of ethanolamine, diethanolamine and morpholine from emulsive ointments.

The effect of addition of lanolin and Span 60 to white vaseline and of their concentration on the pharmaceutical availability of monoethanolamine , diethanolamine and morpholine was investigated. The emulsifier type and its concentration exercise an influence on constant release rates. The liberation of the investigated amines proceeds at almost the same speed as therapeutic substances within the limits from 10 to 30%. The release half life periods showed the same dependence in relation to the content of investigated substances in the ointment.

Biological Availability↗
PubMed1980

[2-(2-Thienyl)morpholines with CNS activity].

The synthesis and pharmacological investigation of 2-(2-thienyl)morpholine and some of its derivatives substituted on the nitrogen are described. The non-substituted compound showed interesting antidepressive properties with a pharmacological profile similar to that of imipramine.

5-Hydroxytryptophan↗