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K Rehse

Publications and source records attributed to K Rehse.

At least 37 records · Page 2Linked to original sources
PubMed1996

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, Part 33. From tetradecane- to octacosanediamines.

Twenty alkanediamines were designed according to structure-activity relationships drawn from previous parts of this series and synthesized. Their general structure is CH3-(CH2)n-CHNH2-(CH2)m-CHNH2-(CH2)n-CH3, (n = 2-10; m = 3-6). Twelve of them inhibited the aggregation of human blood platelets in concentrations between 3-10 micromol/L halfmaximally (Born test, inducer collagen). With increasing m a decreasing n is necessary to achieve the optimum activity. In the most active compounds (7b, 7e, 7p) it is found that m + n = 9. When the nitrogen functions are hydroxyalkylated secondary amines with similar antiplatelet effects are obtained. The conversion of the amino groups into syndronimines is accompanied by the loss of activity. The bisethoxycarbonylderivatives of 7f and 7m (8f, 8m) exhibited antithrombotic effects in rats after oral administration.

Alkanes↗
PubMed1996

New NO-donors with antithrombotic and vasodilating activities, Part 14. 1,3,4-Triazol-1-oles.

Five 1,3,4-triazol-1-oles (5a-f) with different alkyl, aryl, and arylalkyl substituents in 2,5-position were synthesized and tested for their antithrombotic properties. The 2,5-dimethyl derivative 5a was most active. 2 h after administration of 60 mg/kg to rats thrombus formation by a laser beam was inhibited by 42% in arterioles and by 33% in venules. At the same dose the blood pressure of SHR rats was slightly (5%) but significantly decreased even 4 h after application of 5a. This pattern of activities suggests a nitric oxide mediated mechanism of action. 1,1'-Azo-bis-ethanone oxime(7)-the synthetic precursor of 5a-inhibited the aggregation of blood platelet (Born test) with an IC50 = 15 mumol/L.

Animals↗
PubMed1996

New NO-donors with antithrombotic and vasodilating activities, Part 16. 3-Amino-1,2,4-oxadiazol-5-ones as prodrugs for hydroxyguanidines.

Nineteen 4-substituted 1,2,4-oxadiazol-5-ones (6a-s) were prepared as prodrugs for lipophilic hydroxyguanidines which should be metabolized in vivo to nitric oxide. This hypothesis was tested indirectly by measuring the antithrombotic properties of these compounds 2 h after oral administration to rats (60 mg/kg). In mesenteric arterioles seven compounds moderately (> or = 10%) inhibited the formation of thrombi by a laser beam. Maximum effects were observed in 6c (4-pentyl) and 6f (4-benzyl). The lack of activity in the corresponding 2-pentyloxadiazolone 10c, where no formation of nitric oxide seems possible, indirectly suggests that the antithrombotic properties of the title compounds could be mediated by the in vivo formation of nitric oxide.

Animals↗
PubMed1995

New NO-donors with antithrombotic and vasodilating activities, IX: Thiadiazole nitrosimines.

Twenty 1,3,4-thiadiazole-2-nitrosimines and two 1,2,4-thiadiazole-5-nitrosimines were synthesized and assayed in the Born-test for their antiplatelet activity. Only two 1,3,4-thiadiazoles inhibited the aggregation at IC50 < 10 mumol/L. In an in vivo thrombosis model only in arterioles a small inhibition of thrombus formation was observed. The poor test results correspond to a very high chemical stability of the titel nitrosimines.

Animals↗
PubMed1995

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XXV: Interactions of the oligoamine RE 1492 with biomembranes.

The absorption of D-glucose by rat thymocytes is reduced to half of control by 30 mumol/L and decreased to 10% by 100 mumol/L of RE 1492. This is backed by the fact that the absorption of 2-deoxy-D-glucose is inhibited in the same extent. The more hydrophilic oligoamine RE 1888 had an analogous but smaller effect while spermine was ineffective. In a lipid peroxidation model RE 1492 or spermine in a concentration of 100 mumol/L nearly completely inhibited for formation of Fe3+ ions when the phospholipid was mimicked by adenosine monophosphate. This suggests an interaction with negatively charged membrane phospholipids. RE 1888 had an equal but smaller effect. The effect of RE 1492 on lipid order and lipid motility was checked on ovine lymphocyte membranes by fluorescence polarization measurements. The steady state as well as the limiting anisotropy as an expression for lipid order is decreased by rising concentrations of RE 1492. The use of several anthroyloxy stearic acids as fluorescent probes also shows an increased lipid motility in several areas of the membrane bilayer. The use of fluorescent parinaric acid suggests that areas of high regularity, i.e. liquid crystal formation are involved, too.

Animals↗
PubMed1995

New no-donors with antithrombotic and vasodilating activities, X: Antiplatelet and antithrombotic effects of 3-methylsydnone-5-nitrosimine (RE 2047) in combination with ASA, pentoxifylline, and ticlopidine.

The combined effects of the NO-donor RE 2047 with ASA, pentoxifylline, ticlopidine or BM 14515 were determined in vitro (Born-test) and in vivo (rat thrombosis model). The inhibitory effects on platelet aggregation as well as the inhibition of thrombus formation in vivo were over additive and over independent. The combination of 10 mg/kg RE 2047 with the same dose of ASA in arterioles (A) showed 70% inhibition of thrombosis (venoles (V): 40%). The respective values for 10 mg/kg RE 2047 and 10 mg/kg pentoxifylline are 70% (A) and 35% (V). It is concluded that NO-donors in principle are compounds suitable for the combination with antithrombotic drugs of different mechanism of action.

Animals↗
PubMed1995

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XXVII. Inhibition of leucocyte adherence to endothelium by the oligoamine RE 1492C and the NO-donor RE 2047.

The oligoamine RE 1492C (N,N',N"-4-phenylbutyl-1,3,5-benzene-trimethanamine-N,N',N"- triethylcarbamate ) inhibited the electrically provoked leucocyte adhesion to the endothelium of rat mesenteric venoles. An oral dose of 60 mg/kg gave a significant inhibition of 65-78%. This is comparable to effects seen after i.v. administration of iloprost or PGE1, respectively. In the same dosage the NO-donor RE 2047 (3-methyl-N-nitroso-sydnone-5-imine) produced an inhibition of 21-27%.

Animals↗
PubMed1995

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XXVIII: Oligoamines with fluorescent properties. Part C: Fluorescent oligoamines with enhanced hydrophilic properties.

Fifteen fluorescent oligoamines with one or two fluorescent groups and two or three basic N-functions were prepared and tested for antiplatelet activity (Born-test). Five compounds involving three different fluorophores, i.e. 2-fluorenyl, 1-pyrenyl, and 9-phenanthryl, show an IC50 of 7-11 mumol/L. They are suitable to serve as probes in the field of oligoamine-biopolymere interactions.

Amines↗
PubMed1995

New NO-donors with antithrombotic and vasodilating activities, XII: Mesoionic oxatriazoles and related noncyclic nitrosohydrazine derivatives.

Mesoionic 1,2,3,4-oxatriazolimines and the corresponding oxatriazolones were prepared and tested for their antiplatelet and antithrombotic activities. In the Born-test 5-amino-3-phenyl-1,2,3,4-oxatriazolimine chloride inhibited the platelet aggregation halfmaximally in a concentration of 50 nmol/L. Its N-ethoxycarbonyl derivative inhibited thrombus formation in arterioles of rats by 48% (10 mg/kg, 2 h after p.o. administration). These effects appear to be related to the formation of intermediate nitrosohydrazine derivatives. This aspect was supported by the activities in noncyclic nitrosohydrazines (2 compds.), nitrosohydrazones (2) and nitrosohydrazides (11). Five of them exhibited an IC50 < 100 nmol/L in the Born-test. In a thrombotic model strong inhibition of thrombus formation was observed after intravenous application. The 1-nitroso-1-benzylhydrazine even exhibited strong inhibitory effects after oral administration.

Animals↗
PubMed1995

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XXVI: Antiplatelet and antithrombotic effects of the oligoamine RE 1492 in combination with standard and future antithrombotic drugs.

The combined effects of the oligoamine RE 1492 with the NO-donor RE 2047 or ASA, ticlopidine, pentoxifylline and BM 14515 were determined in vitro (Born-test) and in vivo (rat thrombosis model). The effects in vitro were supra additive but over independent. In vivo all combinations showed over additive and over independent inhibition of thrombus formation. The best results were obtained with a combination of 10 mg/kg RE 1492C and 10 mg/kg RE 2047. It inhibited thrombus formation in arterioles (A) by 79% and 36% in venoles (V). The combined effect of RE 1492C and pentoxifylline 10 mg/kg each was 62% (A) or 32% (V), respectively.

Animals↗
PubMed1995

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XXIX: Influence of the antithrombotic oligoamine RE 1492 on the storage of red blood cells, morphology, their potassium and ATP content, hemolysis and viability.

The influence of RE 1492 on the storage of red blood cells (RBCs) was investigated. RE 1492 (c > or = 50 mumol/L) induces the formation of cup cells and hence delays the appearance of echinocytes and crenated spheres in the blood. A concentration of 50 mumol/L RE 1492 drops hemolysis by 50%. At this concentration after 6 h of storage the potassium efflux was enhanced significantly. The ATP concentration was decreased between 12 h and 24 h of storage. During the first 6 h these alterations have no effect on the in vivo viability of RBCs. After 12 h of storage a significant reduction in viability is observed. We suppose that the changes observed are due to the intercalation of RE 1492 in the phospholipid matrix of the RBC membrane, followed by an accelerated substrate turnover in the RBCs.

Adenosine Triphosphate↗
PubMed1995

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XXX: Absorption, organ distribution, and excretion of the oligoamine (+)-(S,S)-1,4-bis-[4-(3-iodo-4-methoxyphenyl)-butylamino]-butane-2,3-di ol and its metabolites.

The pharmacokinetic behaviour of the 131-iodine-labelled title compound 3* and its metabolites in mice was investigated. A two phase, 1st order elimination profile was observed. The second phase is very slow leaving about 35% of radioactivity in the mice even 100 h after i.v. injection, because of high affinity to liver and spleen, caused by strong binding of oligoamines to phospholipids of liver and blood cell membranes. The blood-brain-barrier is not passed. No deep compartments were observed. The doses necessary for antithrombotic effects in vivo were calculated from the blood levels to be 20.5-39.7 mumol/kg for a time interval of 1-6 h after administration.

Animals↗
PubMed1995

Distribution behaviour of 131-iodine labelled trans-N,N'-bis-(ethoxy-carbonyl)-N-[4-(3-iodo-4-methoxyphenyl)butyl]-N' -5- phenylpentyl)-1,4-cyclohexanedimethanamine.

The title compound 9, which is a prodrug, and its active metabolite 7 were labelled with 131I (7*/9*) to investigate their pharmacokinetic behaviour, including the distribution between stomach, gut, muscle, blood, lung, liver, kidney, adrenal gland, heart, and spleen. Four hours after oral administration of 7* to mice only 3% of the dose had been absorbed from the g.i. tract. After 24 h 54% of the radioactivity still is found the gut, predominantly in the small intestine. These results explain why 7, which is a potent antiplatelet drug in vitro, shows no antithrombotic effect in vivo. In contrast, the produg 9/9* is absorbed considerably, i.e. up to 50% in 4 h from the g.i. tract depending on the dose applied and the vehicle used. At doses in the micromolar range the absorption appears to be diffusion limited. The highest concentrations are found in the liver and the kidneys suggesting a first pass effect of 7 followed by renal excretion. From the blood levels achieved, the dose necessary for an antithrombotic effect has been calculated to be about 100 mg/kg. In summary, the N-ethoxycarbonyl derivatives of oligoamines appear to be suitable prodrugs for oral administration of oligoamines.

Animals↗
PubMed1994

Selectivity of sterically fixed tryptamine and 5-methoxytryptamine derivatives for serotonin receptor subtypes, I: Synthesis of N-alkyl- and N,N-dialkyl-3-indolylbicyclo[2.2.1]heptane-2-amines.

Twenty-six title compounds with the ethylamine part of tryptamine or 5-methoxytryptamine fixed in an anticlinal ecliptic conformation were synthesized for assaying them at the different known serotonin receptors. Several alkylation methods have been improved and adapted for the space consuming norbornane system. The structures were fully elucidated by high-field NMR spectroscopy. All 1H- and 13C-signals could be assigned by means of 1H-1H- and 13C-1H-correlation spectroscopy (COSY).

Bridged Bicyclo Compounds↗
PubMed1994

New NO-donors with antithrombotic and vasodilating activities, IV: Chemical reactivity of nitrosimines and its implications for their pharmacologic properties.

Nitrososydnone-5-imines and Thiazole-2-nitrosimines are susceptible to photolytic cleavage of the = N-NO bond. This can be achieved with a tungsten lamp. In water the corresponding syndnone imine salts are formed in 90% yield at 37 degrees C. Only at higher temp. (70 degrees C) ring opening is observed. In methanol about 25% of sydnones are obtained. On the other hand NO. and N2O were detected in the head space of the reaction vials when oxygen was excluded. The formation of N2O from nitrososydnone imine was increased up to elevenfold by glutathione while the amount of NO. was decreased. In the presence of light and thiols soluble guanylate cyclase (s-GC) was stimulated. The results suggest that the nitroxylate anion NO- plays an important role in the stimulation of s-GC.

Fibrinolytic Agents↗
PubMed1994

New NO-donors with antithrombotic and vasodilating activities, V: Oligonitroso sydnone imines.

Nine 4,4'-bis- and four 4,4'-tris-N-nitroso syndrome imines were synthesized. The sydnone imine moiety is connected either by aromatic 1,3-phenylene or 1,3,5-benzene or aliphatic methylene or propylene bridges. Compared to the corresponding sydnone imines the collagen induced platelet aggregation inhibiting activity is increased by several orders of magnitude by the nitroso derivatives. The most potent compound bears a hexyl substituent in 3-position (1d: IC50 = 0.05 mumol/L). These data show that aromatic bridges (1d, 2d) are more favourable than aliphatic ones (4b). This indicates the mutual influence of the nitroso-imino moieties via the aromatic bridges. In the series of 3,3'-bis-nitrososydnone imines (13 compounds) mostly additive effects of the nitroso groups are seen. The activities range from IC50 = 0.2 mumol/L (5i; 1,3-xylene bridge) to IC50 = 8 mumol/L (5b; trimethylene bridge). The differences suggest different affinities to the platelet membrane.

Animals↗
PubMed1994

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XVIII: Oligoamines with fluorescent properties, Part B: Fluorophores in the molecular periphery.

Seventeen N,N'-benzene-1,3-dimethane and nine N,N',N''-benzene-1,3,5-trimethane derivatives with fluorescent properties have been synthesized. Three of them show antiplatelet activities (inducer collagen, IC50 Born-test) in concentrations < 10 mumol/L. They are suitable for interaction studies with biological macromolecules and synthetical and biological membranes. Structure activity relationships demonstrate that heteropolycyclic fluorophores i.e. quinoline, dibenzofurane, or carbazole are favorable substituents for this purpose.

Animals↗