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The authors report the possible interference due to minovine when seeking tricyclic antidepressant derivatives in biological material or pharmaceutical substances. However, their work has shown that kinetic studies using absorption spectrophotometry of the colouration obtained with phosphoric-ceric reagent and thin layer adsorbant chromatography make it possible to eliminate the doubt and identify the Vinca-Minor alkaloid.
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Increased levels of nitric oxide (NO) are found in rejecting renal allografts. Inducible NO synthase (iNOS) in infiltrating monocytes/macrophages could lead to NO bursts. NO may modulate the inflammatory response of early rejection due to its high reactivity with superoxide to yield peroxynitrite. To define the role of iNOS in acute renal allograft, rejection effects of the specific iNOS blockers iminoethyl-lysine and 7-butylhexahydro-1H-azepin-2-imine, monohydrochloride on renal function and morphology were investigated in renal allografts. Lewis rats received Brown Norway grafts with one kidney left in situ. All recipients were treated with low dose cyclosporine-A (2.5 mg/kg BW/day s.c.) to allow moderate rejection. In addition, one group received iminoethyl-lysine (10 mg/kg BW/day gavage) and one group received butylhexahydro-azepin-imine (3.4 mg/kg BW/day i.p.). Sham operated Brown Norway donor rats served as baseline controls. Compared to controls, low dose cyclosporine-A decreased glomerular filtration rate (P<0.05) and numerically increased renal vascular resistance. Adding iminoethyl-lysine to cyclosporine-A improved renal hemodynamics. Adding butylhexahydro-azepin-imine to cyclosporine-A practically restored glomerular filtration rate and renal vascular resistance (P<0.05) to control levels. Grafts treated with cyclosporine-A alone showed vascular, glomerular and tubulointerstitial lesions. Adding iminoethyl-lysine or butylhexahydro-azepin-imine to cyclosporine-A did not significantly reduce vascular and glomerular injury, but diminished tubulointerstitial injury as well as nitrotyrosine staining in tubular epithelium (P<0.05). Thus, adding the iNOS blockers iminoethyl-lysine or butylhexahydro-azepin-imine to cyclosporine-A improved graft function and reduced tubulointerstitial lesions.
Microelectrophoretic methods were used to study the effects on cat spinal neurones of a number of compounds structurally related to the gamma-aminobutyric acid (GABA) agonists muscimol, THIP, and isoguvacine. While N-methylmuscimol was an agonist at bicuculline methochloride-sensitive GABA receptors, somewhat weaker than GABA and THIP, neither N,N-dimethylmuscimol nor N-methyl-THIP interfered significantly with GABA receptors in vivo or binding sites in vitro. Both N,N-dimethylmuscimol and N-methyl-THIP, however, reversibly antagonized the depressant action of glycine. The seven-membered ring analogues of THIP, namely THIA (5,6,7,8-tetrahydro-4H-isoxazolo[5,4-c]azepin-3-ol), THAZ (5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol) and iso-THAZ (5,6,7,8-tetrahydro-4H-isoxazolo[3,4-d]azepin-3-ol), also blocked neuronal inhibition by glycine, iso-THAZ being the most potent compound. The conformationally mobile isomer of THAZ and iso-THAZ, 3-PYOL (5-(3-pyrrolidinyl)-3-isoxazolol), was a much less selective glycine antagonist, being also an antagonist of GABA, 3,4-TAZA (2,5,6,7-tetrahydro-1H-azepine-4-carboxylic acid) and 4,5-TAZA (2,3,6,7-tetrahydro-1H-azepine-4-carboxylic acid), which are amino acid analogues of THIA and THAZ, respectively, and ring homologues of isoguvacine, were also shown to be glycine antagonists. The mechanism of action of the present class of zwitterionic glycine antagonists is unknown. The compounds are much less potent than strychnine.
5H-Benzo[b]naphth[2,3-e]azepine-6,13-diones 4a, 4b and 4H-naphtho[2,3-e]thieno[3,2-b]azepine-5,12-dione (6) were prepared by aldol condensation of phthalic dialdehyde (3) with the fused azepinediones 2a, 2b and 5, respectively. The Schmidt reaction of naphthacene-5,12-quinone (7) yielded 6H-benzo[e]naphth[2,3-b]azepine-7,12-dione (10). Several derivatives of the heterocyclic basic scaffolds 4, 6 and 10 were prepared by standard procedures, e.g. Grignard reaction, deoxygenation with triethylsilane, and sodium borohydride reduction. Evaluation of the synthesized compounds in the NCI in vitro cell line screening revealed a modest antitumor activity without marked cell line selectivity for the majority of the derivatives. The 2-bromo-5H-benzo[b]naphth[2,3-e]azepin-6(13H)-one (19) was the only representative in this series exhibiting a noteworthy growth inhibitory effect for human tumor cells.
Among the hypotensive drugs are the N-alkyldibenz[c,e]-azepines. A representative of this class is 6-allyl-6,7-dihydro-5H-dibenz[c,e]azepine (azapetine). The present investigation involved the preparation of a new series of N-[6,7-dihydro-5H-dibenz[c,e]azepin-6-yl] acid amides namely; acetamide, benzamide, phehyl acetamide, salicylamide and p-hydroxybenzamide derivatives. Another new series of N-[6,7-dihydro-5H-dibenz[c,e]azepin-6-yl]-N-alkyl (or aryl) thioureas was prepared namely ethyl, isopropyl, butyl, cyclohexyl, benzyl, phenyl and o-tolyl thiourea derivatives. IR spectra of the two series of compounds were investigated.
N-[1-(p-Phenoxyphenyl)ethyl]hexahydro-2H-azepin-2-imine hydrochloride (10) and N-[1-(2-dibenzothienyl)-ethyl]hexahydro-2H-azepin-2-imine hydrochloride (22) were found to inhibit in vitro aggregation of human blood platelets induced by ADP with minimal release of procoagulant platelet factor 3. The compounds were selected from a series of substituted alpha-methylbenzyl and tricyclic arylalkyl lactamimides that were free of hypoglycemic and diuretic effects. Compounds 10 and 22, as well as N-[1-(1-naphthyl)ethyl]hexahydro-2H-azepin-2-imine hydrochloride (I) and N-(2,2-diphenylpentyl)hexahydro-2H-azepin-2-imine hydrochloride (II), were evaluated for effects on ADP-induced platelet aggregation after repeated oral administration to guinea pigs. Compound II (RMI 12,366A) showed in vivo activity in this system 2 h after the last of four daily doses of 100 mg/kg po.
The effects of the three azepine compounds, B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepine), B-HT 933 [2-amino-6-ethyl-5,6,7,8-tetrahydro-4H-oxazolo[4,5-d]azepine; azepexole] and B-HT 958 (2-amino-6-(p-chloro-benzyl)-4H-5,6,7,8-tetrahydrothiazolo[5,4-d]a zepine) on electrically evoked overflow of 3H-noradrenaline were studied. Slices from parietal cortex (Cx) or nucleus anterior hypothalami (nah) were incubated with 3H-noradrenaline, superfused at 23 degrees C or 37 degrees C in the presence of the noradrenaline uptake inhibitor desipramine (3 mumol/l) and field stimulated at frequencies of 0.3 or 3 Hz. At 37 degrees C/0.3 Hz, B-HT 920 and B-HT 933 concentration-dependently decreased the evoked overflow of tritium in both regions studied, whereas B-HT 958 had no effect. In a second set of experiments each drug was tested under three additional experimental conditions, i.e. 37 degrees C/3 Hz, 23 degrees C/0.3 Hz and 23 degrees C/3 Hz. Increasing the stimulation frequency to 3 Hz or lowering the superfusion temperature to 23 degrees C reduced the effects of B-HT 920 (1 mumol/l) and B-HT 933 (10 mumol/l) as compared to the effects at 37 degrees C/0.3 Hz. When tested at 23 degrees C/3 Hz, both drugs did not significantly affect the evoked overflow of tritium in the Cx or the nah. In contrast, B-HT 958 (10 mumol/l), caused a facilitation of evoked overflow in both regions when the higher stimulation frequency or the lower superfusion temperature was used. Its release-enhancing action was most pronounced at 23 degrees C/3 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)
As part of a larger search for potent as well as selective inhibitors of dihydrofolate reductase (DHFR) enzymes from opportunistic pathogens found in patients with AIDS and other immune disorders, N-[(2,4-diaminopteridin-6-yl)methyl]dibenz[b,f]azepine (4a) and the corresponding dihydrodibenz[b,f]azepine, dihydroacridine, phenoxazine, phenothiazine, carbazole, and diphenylamine analogues were synthesized from 2, 4-diamino-6-(bromomethyl)pteridine in 50-75% yield by reaction with the sodium salts of the amines in dry tetrahydrofuran at room temperature. The products were tested for the ability to inhibit DHFR from Pneumocystis carinii (pcDHFR), Toxoplasma gondii (tgDHFR), Mycobacterium avium (maDHFR), and rat liver (rlDHFR). The member of the series with the best combination of potency and species selectivity was 4a, with IC(50) values against the four enzymes of 0. 21, 0.043, 0.012, and 4.4 microM, respectively. The dihydroacridine, phenothiazine, and carbazole analogues were also potent, but nonselective. Of the compounds tested, 4a was the only one to successfully combine the potency of trimetrexate with the selectivity of trimethoprim. Molecular docking simulations using published 3D structural coordinates for the crystalline ternary complexes of pcDHFR and hDHFR suggested a possible structural interpretation for the binding selectivity of 4a and the lack of selectivity of the other compounds. According to this model, 4a is selective because of a unique propensity of the seven-membered ring in the dibenz[b,f]azepine moiety to adopt a puckered orientation that allows it to fit more comfortably into the active site of the P. carinii enzyme than into the active site of the human enzyme. Compound 4a was also evaluated for the ability to be taken up into, and retard the growth of, P. carinii and T. gondii in culture. The IC(50) of 4a against P. carinii trophozoites after 7 days of continuous drug treatment was 1.9 microM as compared with previously observed IC(50) values of >340 microM for trimethoprim and 0.27 microM for trimetrexate. In an assay involving [(3)H]uracil incorporation into the nuclear DNA of T. gondii tachyzoites as the surrogate endpoint for growth, the IC(50) of 4a after 5 h of drug exposure was 0.077 microM. The favorable combination of potency and enzyme selectivity shown by 4a suggests that this novel structure may be an interesting lead for structure-activity optimization.
Assembly of the azepine ring of xantheno[9,1-cd]azepines by electrophilic cyclization of sulfonamide acetals provides access to clavizepine analogues in the form of 2,12b-dihydro- or 4-hydroxy-2,3,4,12b-tetrahydro-1H-xantheno[9,1-cd]azepines, in the latter case producing the trans derivative stereoselectively. Binding assays for clavizepine and analogues at adrenergic, dopaminergic, and serotonergic receptors are reported.
The bicyclic 5-isoxazolol zwitterions 4,5,6,7-tetrahydroisoxazolo[4,3-c] pyridin-3-ol (3, iso-THPO), 5,6,7,8-tetrahydro-4H-isoxazolo [4,3-c]azepin-3-ol (12, iso-THAO), and 5,6,7,8-tetrahydro-4H-isoxazolo [3,4-c]azepin-3-ol (13, iso-THIA), which are structurally related to the glycine antagonist 5,6,7,8-tetrahydro-4H-isoxazolo[3,4-d]azepin-3-ol (iso-THAZ), have been synthesized and tested biologically. All of these compounds were glycine antagonists approximately equipotent with iso-THAZ during microelectrophoretic ejection near cat spinal neurons. In contrast to iso-THAZ, which also interacts with 4-aminobutyric acid (GABA) receptors in rat brains, neither 12 nor 13 show any significant affinities for GABA binding or uptake mechanisms in vitro. The glycine antagonist 3 was, however, shown also to be a moderately potent inhibitor of GABA uptake. The structure of 12 was established by an X-ray analysis. The bond lengths of the 5-isoxazolol anionic moiety of 12 are in agreement with a pronounced delocalization of the negative charge of this compound.
PURPOSE: Newly designed antiepileptic drugs (AEDs) are being evaluated for their efficacy in preventing seizures and for their toxic profiles. We investigated and compared the toxic effects of two dibenz[b,f]azepine derivatives with anticonvulsant activity, 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide (BIA2-024) and (S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f] azepine-5-carboxamide (BIA2-093), with the structurally related compounds carbamazepine (CBZ) and oxcarbazepine (OXC), both in current use for the treatment of epilepsy. METHODS: Primary rat hippocampal neurons were used to evaluate neuronal morphology and biochemical changes induced by the AEDs used in this study. Immunocytochemical staining against MAP-2 was used to evaluate neuronal morphology. Reactive oxygen species (ROS) and changes in mitochondrial membrane potential (Psim) were measured by fluorescence techniques. Intracellular adenosine triphosphate (ATP) levels were quantified by high-performance liquid chromatography (HPLC). RESULTS: Hippocampal neurons treated for 24 h with CBZ or OXC (300 microM) showed degeneration and swelling of neurites, but this effect was not observed in neurons treated with BIA 2-024 or BIA 2-093 (300 microM). ROS production also was increased in neurons treated with OXC, but not in neurons treated with the other AEDs. ATP levels were significantly decreased only in neurons treated with OXC, although the energy charge was not altered. Furthermore, OXC led to a decrease of Psim. CONCLUSIONS: In all parameters assayed, OXC was more toxic than the other AEDs used. Because the new putative AEDs have previously been shown to have an efficacy in preventing seizures similar to that of CBZ and OXC, and are less toxic to neuronal cells, they may be considered as alternatives to the current available therapies for the treatment of epilepsy.
Four alcoholic metabolites of (+-)-3-chloro-5-[3-(2-oxo-1,2,3,5,6,7,8,8a-octahydroimidazo[1,2-a] pyridine-3-spiro-4'-peperidino)propyl]-10,11-dihydro-5'-dibenz[b,f ] azepine(mosapramine), a new antipsychotic drug, were synthesized in order to determine their chemical structures. A mixture of 10-ethoxy-3-chloro-10,11-dihydro-5H-dibenz[b,f]azepine and 11-ethoxy isomer was used as a starting material. Isomeric intermediates, i.e. 10-oxo-3-chloro-5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine and 11-oxo isomer, were separated by chromatography with silica gel. The metabolites were obtained by NaBH4 reduction of the corresponding 10-oxo or 11-oxo compounds followed by introduction of spiro-piperidine moieties into propyl side chain.