Biomedical subjects

K Rehse

Publications and source records attributed to K Rehse.

At least 55 records · Page 3Linked to original sources

PubMed1994

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XXIII: Influence of the oligoamine RE 1492 on the deformability of red blood cells.

The influence of the oligoamine RE 1492 on the deformability of Red Blood Cells (RBCs) was measured with the micropipette aspiration technique and the capillary rigidometer. The maximal cell flow resistance (MCFR) and the apparent elastic membrane shear modulus mu were increased by 45% at RE 1492 concentrations > 10 mumol/L. There was a decrease of the surface/volume ratio of 6% at RE 1492 concentrations of 25 mumol/L. The qualitative analysis of the polypeptide pattern of membranes and extracted membranes of human RBCs suggests that the reduction of deformability is due to an increased affinity of skeletal proteins to the cytosolic part of the membrane. RE 1492 caused a decrease of osmotic hemolysis by 80% at concentrations of 8 mumol/L.

Anticoagulants↗

PubMed1994

New NO-donors with antithrombotic and vasodilating activities, VI: thiazole-2-nitrosimines.

24 new thiazole-2-nitrosimines were prepared and described by means of spectroscopical methods (NMR, IR, MS, UV). At pH 7 in cell free systems as well as in platelet rich plasma the compounds are stable against hydrolysis and do not react with the platelet glutathione. The chemical stability is underlined by the mass spectra: M+. is of high intensity and sometimes even forms the base peak (e.g. 8a). Thermal elimination of N2 is of minor importance. The =N-NO bond in solution is susceptible to cleavage by visible light. The metabolite so formed is able to inhibit the platelet aggregation induced by collagen (Born-test). Five compounds exhibit this activity in concentrations below 10 mumol/L (IC50). This is due to the release of a NO species, as could be demonstrated by the stimulation of soluble guanylate cyclase in a cell free system (e.g. 8a, KM = 72 mumol/L). In vivo the nitrosimines show antithrombotic properties. Two h after a single oral dose of 8g (60 mg/kg) a 57% inhibition of the laser induced thrombus formation in the mesenteric arterioles of rats is observed. After 8 h a 43% inhibition still is seen.

Animals↗

PubMed1994

New NO-donors with antithrombotic and vasodilating activities, VII: Z/E-isomerism in thiazole- and 1,3,4-thiadiazole-2-nitrosimines.

In thiazole- (23 compounds) and 1,3,4-thiadiazole-2-nitrosimines (20 compounds) Z/E-isomers were described by 1H-NMR-spectroscopy. There is a mutual conversion of the isomers. The coalescence temp. (Tc) mostly is 310 K. In the thiazole series, however, for five compounds higher energy barriers are observed. This is due to substituents in 4-position with electron withdrawing properties. The Tc is increased when the compounds are dissolved in water instead of DMSO. Hereby it is concluded that the isomers have Ze or Ee configuration. It is made probable that the low field signal for the substituent in 3-position corresponds to the Ze-isomer, which has a slight preference. The free enthalpy of rotation, calculated approximately, is between 56.0 (1m) and 73.7 kJ/mol (1r).

Fibrinolytic Agents↗

PubMed1994

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XXIV: Interactions between oligosydnone imines and albumin or phospholipids.

Oligosydnone imines are strongly bound to albumin (alpha < 1%) in pure water. In saline, however, this effect is abolished (alpha approximately 80%). 4,4'-Propylene-bis-3-hexyl-sydnone-5-imine hydrochloride (1) moderately binds to phosphatidylcholine liposomes (PC, alpha approximately 34%). This is increased by phosphatidylethanolamine (PE). In PC/PE vesicles alpha is about 7%. The binding is further enhanced by the incorporation of negatively charged phospholipids (PL) like phosphatidylserine (PS). In PC/PE/PS liposomes complete binding of 1 can be achieved. This holds especially true if the composition of the liposomes is similar to the PL composition of platelet membranes. The results suggest that the antiplatelet activity of 1 is mediated by the bindings to negatively charged PL in the platelet membrane.

Albumins↗

PubMed1994

New NO-donors with antithrombotic and vasodilating activities, VIII: Benzothiazole-2(3H)-nitrosimines.

Thirty title compounds were prepared and tested for their antiplatelet activity in the Born-test. Five nitrosimines inhibit the aggregation induced by collagen in concentrations below 10 mumol/L halfmaximally. Four compounds were investigated in an in vivo thrombosis model. An inhibition of thrombosis between 29 and 53% was observed in mesenteric arterioles of rats 2 h after p.o. administration (60 mg/kg). The effect in venoles was less pronounced (10-22%). For one compound these effects could still be demonstrated 4 h after oral application.

Animals↗

PubMed1993

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XIX: 4,4'-Phenylene-bis-sydnone imines.

Fourteen 4,4'-m-phenylene- and two 4,4'-p-phenylene-bis-sydnone imine hydrochlorides have been synthesized. All compounds exhibited good solubility in water. In the m-series the 3-(3-phenylpropyl)-derivative 5c and the 3-hexyl compound 5l showed antiplatelet activities at or below 10 mumol/L (IC50, Born-test with collagen). The corresponding p-compounds had the same (6l) or slightly lower (6c) activity. No effect on the fibrin formation (Quick-test) could be observed.

Anticoagulants↗

PubMed1993

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XX: 4,4',4''-(1,3,5)-benzene-tris-sydnone imines.

The synthesis of ten tris-sydnone imine derivatives, unknown up to now, is described. All compounds are alkyl or arylalkyl substituted in 3-position of the sydnone imine. The most powerful agent was the 3-propyl derivative 6c. It inhibits the aggregation of human platelets induced by collagen in a concentration of 1 mumol/L half maximally. Its N-ethoxycarbonyl derivative 7c, which was designed as a prodrug, showed only small antithrombotic effects in rats. The reason for this low degree of activity is discussed.

Animals↗

PubMed1993

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XXI: 4,4'-Alkylene-bis-sydnone imines.

Two methylene-, seven ethylene-, eleven propylene- and two 4,4'-butylene-bis-sydnone imines have been synthesized and tested for their antiplatelet (Born-test, collagen) and anticoagulant (Quick-test) activity in vitro. The most active compounds were found in the ethylene and propylene series. The most favourable substituents in 3-position of the sydnone were hexyl to octyl or phenylethyl to phenylbutyl groups. Six compounds exhibit an IC50 < or = 10 mumol/L against platelet aggregation. Three compounds showed an IC75 < or = 200 mumol/L concerning the fibrin formation (Quick delta t > or = 7 s).

Anticoagulants↗

PubMed1993

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XXII: Bisoxazol-, bisimidazol-, bisthiazol- and oligo-1,2,4-thiadiazolimines.

One mesoionic 4,4'-propylene-bis-oxazol-5-imine (5), two 2,2'-m-phenylene-bis-imidazol-4-imines (9a,b), five 4,4'-benzene-bis-(and tris)-thiazol-2-amines (13a,b, 14a-c) and 14 3,3'-benzene-bis-(and tris)-1,2,4-thiadiazolimines (18a-o) were synthesized and assayed for their antiplatelet and anticoagulant activities. The most potent compound was the tris-thiadiazole derivative 18m which inhibited the aggregation of platelets induced by collagen at a concentration of 10 mumol/L by 50 percent (Born-test). No anticoagulant effects (Quick-test) were observed up to 400 mumol/L. In the thiazolamine series combined antiplatelet and anticoagulant activities were seen.

Anticoagulants↗

PubMed1993

New NO-donors with antithrombotic and vasodilating activities, I: 3-Arylalkyl-N-nitroso-5-sydnone imines.

Nine nitrosimino title compounds were prepared. They inhibit the aggregation of human platelets induced by collagen with an IC50 = 0.7--33 mumol/L. The most active substance is the 3-phenylethyl derivative 6b. The in vitro effect is mediated by an active metabolite which is formed by a photochemical reaction in the aggregometer. As the corresponding and so far unknown sydnone-5-cyanimines have no effect on platelets the metabolite is most certainly a NO-species. The activity of the sydnone-5-nitrimine 5b is in the same order of magnitude (IC50 = 7.5 mumol/L) as in the nitrosimines of type 6. The most active compound 6b was investigated for antithrombotic properties in a thrombosis model, where the thrombus formation was induced by a laser-beam. 2 h after oral administration of 60 mg/kg of 6b to rats in venoles a 28% inhibition of thrombin formation was found. In arterioles this effect is more evident and a 48% inhibition is seen (the thrombus formation index is 2.6 and 3.9, respectively). These results suggest that the active metabolite is formed as well in vivo.

Fibrinolytic Agents↗

PubMed1993

New NO-donors with antithrombotic and vasodilating activities, II: 3-alkyl-N-nitroso-5-sydnone imines.

Fifteen 3-alkyl-, four 3-cycloalkyl-N-nitroso-5-sydnone imines and five 3-alkyl-N-nitro-5-sydnone imines were synthesized and their ability to inhibit platelet aggregation induced by collagen (Born-test) was studied in vitro. Dependent on the chemical structure, the IC50-values for the inhibition of platelet aggregation were in the range of 0.2-140 mumol/L. It is suggested that this scale reflects different binding properties of the nitrosimines with respect to the platelet membrane. Highest activities were observed for the 3-hexyl (2f) and the 3-cyclohexyl (2p) derivative. Three nitrimines (3e, 3f, 3i) also showed IC50 values below 10 mumol/L. For the nitrosimines 2a, 2f, and 2m antithrombotic activity was demonstrated in vivo. They inhibited laser induced arterial thrombosis in anesthetized rats up to 70% two h after oral administration. In conscious renal-hypertensive dogs, the decrease in systolic blood pressure and left ventricular enddiastolic pressure suggests an antianginal activity of the compound 2a similar to that of molsidomine (M). The smoother onset and the longer duration of action of the new compound as compared to M could be a significant advantage of 2a in the therapy of angina pectoris.

Animals↗

PubMed1993

Selectivity of sterically fixed tryptamine and 5-methoxytryptamine derivatives for serotonin receptor subtypes, II: Structure-activity relationships and in vitro pharmacology of N-alkyl- and N,N-dialkyl-3- indolylbicyclo-[2.2.1]-heptane-2-amines.

Twenty-four norbornane analogues of tryptamine and 5-methoxytryptamine were investigated for affinity at 5-HT2 receptors of the rat tail artery and proved to be weak non-competitive antagonists of 5-HT. Compound 12 which displayed a marked depression of the concentration-effect curves, was examined for potential interaction with the allosteric binding site of the 5-HT2 receptor. The effects elicited by 12, in the presence and absence of the allosteric activator ketanserin, were atypical and must be attributed to a mechanism, unknown up to now. In radioligand displacement experiments binding data for a set of nine compounds were determined at 5-HT1-like, 5-HT2 and 5-HT3 receptors, indicating subtype selectivity for some analogues. The binding affinity of 8 at 5-HT3 receptors which was comparable with the affinity of the selective 5-HT3 agonist 2-methyl-5-HT, could not be demonstrated on the longitudinal muscle strip of the guinea-pig ileum, partially due to the M3 antimuscarinic activity of 8. Functional studies on the rat oesophageal tunica muscularis mucosae did not reveal 5-HT4 agonist properties for two analogues of 5-methoxytryptamine (8, 16).

5-Methoxytryptamine↗

PubMed1993

New NO-donors with antithrombotic activities and vasodilating activities, III: 3,4-disubstituted N-nitroso-5-sydnone imines.

38 title compounds have been synthesized. They bear a wide variety in substituents including alkyl-, aryl-, arylalkyl-, and styryl groups. The anti-platelet activities elucidated in the Born-test with collagen cover more than two orders of magnitude (IC50 = 0.3-45 mumol/L). These effects depend on the presence of the N-NO-group. This is shown by comparison with the corresponding sydnone imines, sydnone cyanimines, and sydnones. The most suitable substituents were phenylethyl, styryl, and hexyl at either position of the molecule. Seven compounds, most of them styryl derivatives, have IC50 values below 1 mumol/L. It is suggested that the differences in activity are connected with the ability of the compounds to bind to the platelet membrane.

Animals↗

PubMed1992

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XVII: Oligoamines with fluorescent properties. Part A: Fluorescent bridged nitrogen functions.

Eleven dimethanamines and one disydnonimine with fluorescent properties have been synthesized. All of them show antiplatelet activities (IC50, Born-test) in concentrations between 14-75 mumol/L. Five of them inhibited fibrin formation induced by thromboplastin by more than 75% in a 200 mu molar concentration. Both effect do not run parallel. The most space consuming fluorophores show the smallest inhibition of the platelet aggregation. Best results were obtained with an azulene, acenaphthene or naphthalene moiety between the two basic nitrogen functions.

Anticoagulants↗

PubMed1991

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XIV: Branched aliphatic and alicyclic triamines and tetramines.

Twenty-four triamines and three tetramines were synthesized. Seventeen triamines inhibited platelet aggregation induced by collagen at a concentration below 10 mumol/L (IC50). Ten triamines in a 100 mumolar concentration inhibited fibrin formation induced by thromboplastin by more then 75%. Both effects do not run parallel. They are strongly dependent from the steric and lipophilic properties of the title oligoamines. The tetramines were nearly inactive.

Anticoagulants↗

PubMed1991

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XV: Antithrombotic effect of selected oligoamines in rats.

Oligoamines which exert antiplatelet and anticoagulant properties in vitro show as well antithrombotic effects in mesenteric arterioles and venoles of rats. The formation of thrombi in these vessels was induced by a laser beam and quantified by the thrombus formation index (TFI). The most potent compound RE 1492 already reduced the formation of thrombi after i.v. administration of 1 mg/kg significantly. After oral administration, however, only a minor effect even after a 200 mg/kg dose is observed. This suggests that the oligoamine was poorly absorbed from the gastrointestinal tract. The tricarbamate of RE 1492 (identical to RE 1492 C), however, was a suitable prodrug. Eight hours after a single oral dose of 10 mg/kg significant antithrombotic properties in arterioles and venules were seen. (TFI = 3.63 (A), 1.77 (V); control: 1.76 (A), 1.29 (V).) After p.o. application of 30 mg/kg RE 1492 C the onset of activity is after 2 h (TFI = 3.44/1.48). A maximum effect is reached after 4 h (TFI: 4.43/2.84) and maintained up to 24 h (TFI = 4.49/2.45). After 48 h the effect in arterioles is still significant (p less than 0.05, chi 2-test). The results obtained with five other carbamates (RE 2029 C, RE 1964 C, RE 2120 C, RE 2112 C, and RE 1981 C) 4 h after p.o. administration in general show a stronger effect in arterioles than in venules which is in the same range as in RE 1492 C.

Amines↗

PubMed1991

Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XVI: Cytostatic and cytotoxic side effects of oligoamines.

Selected synthetic oligoamines were able to inhibit (IC50) the growth of leukemic L 1210 cells in concentrations between 4-10 mumol/L. The essential structural features were at least two basic nitrogen functions in suitable distance, substituted with arylalkyl or alkyl groups. The favorable chain length is about eight carbon atoms. The cytostatic effect is complete after 30 min and cannot be washed out with buffer. Viability measurements showed that the leukemic cells were killed in a time dependent manner. As no influence on the cell nucleus could be observed this is most probably due to interaction with the cell membrane. When high local concentrations are applied in vivo, the oligoamines are toxic because of cytolytic properties. This toxicity can be overcome by administration of suitable prodrugs (LD50 greater than 1000 mg/kg).

Animals↗

PubMed1990

[Anti-aggregatory and anticoagulant properties of oligoamines. 11. Oligoamines with two primary amine groups].

Ten branched alpha,omega-alkanediamines with two primary amino groups have been synthesized and tested for their antiplatelet and anticoagulant effects. Seven of them inhibited the platelet aggregation induced by collagen at an IC50 ranging from 5-11 mumol/L. In concentrations up to 400 mumol/L the one stage thromboplastin time was only slightly prolonged (delta t less than 7s).

Amines↗