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PubMed1975

[Studies on the osmotic resistance and the viability of amidinated erythrocytes].

The present studies are concerned with properties of amidinated erythrocytes. The reactions of dimethyladipimidate with proteins in solution and red blood cells, respectively, result in an intermolecular cross-linking. Following an amidination of human serum albumin or human gamma-globulin cross-linked products of increased molecular weight have been demonstrated by polyacrylamide gel and immune electrophoresis. Human erythrocytes previously amidinated intensely, exhibit a restricted motility of membrane particles and cross-linked hemoglobin. Intensely amidinated erythrocytes are resistant against distilled water, and they do no longer agglutinate. The findings presumably indicate an increased permeability of the amidinated red cell membrane. The glycolytic activity was found to be normal in moderately amidinated erythrocytes. In comparison with normal red blood cells, previously moderately amidinated erythrocytes of the rat become sequestered more quickly after re-injection into the vascular system.

Amidines↗

PubMed1975

Effect of amidination of lysyl residues on the oxygen affinity of human hemoglobin. Specificity of methyl acetimidate for lysine C5(40)alpha.

Treatment of human oxyhemoglobin with methylacetimidate results in selective amidination of the epfilon-amino group of lysin C5(40)alpha. The modified hemoglobin exhibits increased oxygen affinity, high cooperatively, and normal Bohr effect. Hybrid molecules containing amidinated beta chains and normal alpha chains have normal ligand-binding properties, whereas hybrid molecules containing amidinated alpha chains have ligand-binding properties identical with fully amidinated hemoglobin. Amidination of deoxyhemoglobin produces only minimal changes in ligand-binding properties. We propose that amidination of lysine C5(40)alpha prevents its participation in the salt bond with histidine HC3(146)beta in deoxyhemoglobin, thus shifting the allosteric equilibrium in favor of the high affinity oxy conformation.

Amino Acid Sequence↗

PubMed1976

[Intravital survival and deformability of weakly amidinated rat erythrocytes].

Rat erythrocytes previously labelled with 51Cr were treated with 0.1 mM and 0.5 mM dimethyladipic imidate (ADE) pH 9.5, respectively, or with borate buffer pH 9.5 for 15 minutes each. After reinjection into rats of amidinated or nonamidinated erythrocytes their elimination form the streaming blood was followed for 50 days (0.1 mM ADE) or 38 days (0.5 mM ADE). During the 1st day about 10% of amidinated erythrocytes were sequestered. There was no increased initial elimination rate of borate incubated red blood cells detectable. During the following period the elimination rate of erythrocytes amidinated with 0.5 mM ADE was slightly greater than in the case of erythrocytes treated with 0.1 mM ADE. The mean life span of 0.5 mM ADE-erythrocytes was shorter compared with the controls and with 0.1 mM ADE-erythrocytes. Red blood cells previously treated with 0.5 mM ADE are significantly less deformable. Presumably, the stiffness of amidinated erythrocytes causes their increased elimination rate.

Adipates↗

PubMed1979

Cyclic amidine inhibitors of indolamine N-methyltransferase.

Syntheses of a large number of mono- and bicyclic, as well as a few tricyclic, amidine derivatives related to 2,3,4,6,7,8,-hexahydropyrrolo[1,2-a]pyrimidine (DBN) are reported. In vitro potencies for inhibition of the enzyme indolamine N-methyltransferase (INMT) from rabbit and human lung are presented. Four bicyclic amidine derivatives and 11 monocyclic derivatives were found to be equal or superior to DBN in in vitro potencies. With the bicyclic amidines, increasing ring size or introduction of substituents reduced activity. Among the monocyclic analogues, the most potent representatives were five- or six-membered systems with an exocyclic imino group, combined with methyl of ethyl substituents on the endocyclic nitrogen. Introduction of additonal substituents decreased inhibitory potency. 2,3,5,6-Tetrahydro-8H-imidazo[2,1-c][1,4]thiazine and 3-methyl-2-iminothiazolidine have been shown to cause inhibition of lung INMT when administered orally to rabbits.

Amidines↗

PubMed1977

[The possibility of use of amidinated human erythrocytes as agglutinin adsorbents in hemagglutination tests].

This study is concerned with the agglutinability of amidinated human erythrocytes. Amidinated erythrocytes behave like an immuno-adsorbent. Following the adsorption of an agglutinin, amidinated erythrocytes agglutinate specifically with native red blood cells or with native eukaryotic cells, if the glycocalyx of these native cells is provided with the respective agglutinin receptor groupings.

Amidines↗

PubMed1975

Inhibition of phenylalanyl-tRNA synthetase by aromatic guanidines and amidines.

Aromatic guanidines and amidines were investigated for their ability to inhibit phenylalanyl-tRNA synthetase from E. coli B. 2-Phenylacetamidine (1), benzylguanidine (2), and N-benzylbenzamidine (3) are competive inhibitors with respect to phenylalanine, binding nearly as well as the substrate, The remainder of the inhibitors was unexpectedly found to be noncompetitive, indication the presence of a secondary binding site on the enzyme. Inhibition by these compounds appears to be specific for phenylalanyl-tRNA synthetase and requires the presence of a phenyl ring as well as the amidine or guanidine moiety.

Amidines↗

PubMed1976

[Mechanical resistance of amidinated human erythrocytes].

The amidination reactions by means of dimethyl adipimidate (0.25-10.0 mM) or dimethyldodecane-imidate (0.1-1.0 mM) cause an alteration of the mechanical resistance of red blood cells. Low amidination results in peripheral cross-links of erythrocytes whose mechanical resistance increase relative to borate buffer treated cells. Increasing cross-linking reduces the mechanical resistance of erythrocytes, which finally appears to have become restored. The final state, however, is characterized by an almost complete cross-linking of the cell, which than no longer behaves like an osmometer.

Amidines↗

PubMed1979

Amidination of amino groups of aldehyde reductase from human liver.

Amidination of human liver aldehyde reductase (alcohol:NADP+ oxidoreductase, EC 1.1.1.2) with monofunctional n-alkane methylimidates increased the enzymic activity by 10--30%, whereas analogous bifunctional imidoesters caused a loss of activity of about 80%. Both effects were prevented in the presence of the coenzyme NADPH or NADP+, but not of the substrate 4-nitrobenzaldehyde. Amidination increased the apparent Michaelis constant of both the coenzyme (up to 20-fold) and the substrate (about 5-fold). Bifunctional imidoesters with at least 4 carbon atoms between the functional groups (approx. 0.7 nm) crosslinked the enzyme intramolecularly. This reaction was retarded in the presence of the coenzyme, whereas 4-nitrobenzaldehyde had no effect. The results suggest the presence of reactive amino groups at the coenzyme binding site of aldehyde reductase.

Alcohol Oxidoreductases↗

PubMed1977

Effects of amidination and chemical cross-linking on human factor VIII (antihemophilic factor).

The bifunctional reagent dimethyl suberimidate, reacting with primary amino groups of proteins, was used to cross-link highly purified human factor VIII. Reaction products were reduced with beta-mercaptoethanol or treated with Rhizopus arrhizus triglyceride lipase. The proportions of the dissociated subunits and their oligomers were calculated from the relative staining intensities of individual bands following polyacrylamide electrophoresis in the presence of sodium dodecyl sulfate. Low concentrations of dimethyl suberimidate (up to 0.5 mM) produced covalently linked dimers which retained full functional (coagulant and von Willebrand factor) activities. Treatment with increasing concentrations of dimethyl suberimidate resulted in an almost simultaneous appearance of both trimeric and tetrameric species, suggesting the existence of specific intra-dimer contacts. A parallel decrease of functional activities was observed at higher concentrations of dimethyl suberimidate. A monofunctional reagent (ethyl acetimidate), reacting similarly with primary amino groups, amidinated factor VIII at rates similar to dimethyl suberimidate. Up to 40% amidinated factor VIII retained full biological activities. We conclude that the most reactive lysine residues are not involved in the active sites responsible for either coagulant or von Willebrand activity.

Blood Coagulation↗

PubMed1976

Aromatic Tris-amidines. A new class of highly active inhibitors of trypsin-like proteases.

A number of novel aromatic Tris-amidines have been synthesized and investigated for their antiproteolytic property. The basic structure of the compounds is that of mesitylene where each of the methyl groups has been substituted with a 3- or 4-amidinophenoxy moiety. The compounds displayed considerable activity against trypsin (EC 3.4.21.4) and thrombin (EC 3.4.21.5), but proved most effective against porcine pancreatic kallikrein (EC 3.4.21.8). With this enzyme a Ki value of 2.43-10(-8) M was recorded for alpha,alpha',alpha''-tris(4-amidino-2-bromophenoxy)mesitylene at pH 8.1 and 37 degrees C. The most potent thrombin inhibitor, alpha,alpha',alpha''-tris(3-amidinophenoxy)mesitylene, had a Ki value of 6.51-10(-7) M and was also a strong overall anticoagulant. The inhibitors were able to interfere with the kinin release by human plasma kallikrein at concentrations as low as 1-10(-10) M. However, despite this remarkable antikallikrein effect and the known importance of plasma kallikrein in the activation of Hageman factor (factor XII), the compounds had only little influence on the early stages of blood coagulation.

Amidines↗

PubMed1975

Amidines and related compounds. 6. Studies on structure-activity relationships of antihypertensive and antisecretory agents related to clonidine.

Correlations of antihypertensive and antisecretory activities with various structural modifications of the antihypertensive agent clonidine (2-(2,6-dichlorophenylimino)imidazolidine) are described. Eleven chemical classes of compounds containing an "amidine" moiety were prepared in this study. The antihypertensive activity of these compounds was evaluated in metacorticoid hypertensive rats and unanesthetized neurogenic hypertensive dogs following oral administration. Antisecretory activity was evaluated in fistula rats by measuring pH and volume of gastric secretion. Two compounds, 2-(2,6-dimethylphenylimino)imidazolidine and 2-(2,6-dichlorophenylimino)pyrrolidine, are particularly effective antisecretory agents with minimal antihypertensive activity.

Amidines↗

PubMedDate not supplied

New amidine derivatives of indole.

A series of new derivatives of indole of expected biological activity was prepared. Amidines 7 and 8 were obtained from the corresponding nitriles 3 and 4 and iminoethers 6.

Amidines↗

PubMed1975

[Relationships between structure and the noradrenaline depleting effects of guanidine and amidine derivatives (author's transl)].

In guinea pigs we studied the noradrenaline (NA) depletion in the sympathetic nerve terminals of the heart exerted by 24 derivatives of guanidine and amidine; the effects of these substances being considerably similar in their chemical structure were compared to those of reserpine, guanethidine, guanoxan and cyclazenin. Substitution of the free guanidine group to give an imidazoline or imidazolidine ring diminished the activity of the compounds. If the benzodioxane ring of guanoxan was "opened" to give a diether of catechol, the activity of the substances was not altered. We also observed a NA depletion after injection of some guanidine derivatives substituted with piperazine. The elongation of the aliphatic chain between guanidine and the aromatic substituent considerably decreased the activity of the compounds.

Amidines↗

PubMedDate not supplied

Studies on pyrazine derivatives. Part VII. Synthesis and tuberculostatic activity of some pyrazine amidines and amidoximes.

In the reaction of 2-cyano-6-alkylaminopyrazines with sec. amines in the presence of anhyd. AlCl3 amidines 1-13 were obtained. From pyrazine-2-imidoesters, 2-cyano-pyrazines and pyrazine-2-carbothioamides and hydroxylamine, amidoximes 14-49 were easily prepared. These new compounds were, however, of little tuberculostatic activity (MIC between 31.5-2000 mug/cm3).

Amidines↗

PubMed1978

[Hydrolysis of the amidine analogs of penicillins].

The products of the hydrolytic degradation of 6-beta-(hexahydro-IH-azepenyl-1)methylenamino) penicillanic acid, 6-beta-(N,N-dimethylformamidino-N1)-penicillanic acid and 6-beta-(morpholinyl-1)methylenamino penicillanic acid were identified with the method of thin-layer chromatography and paper electrophoresis in neutral, acid and alkaline solutions and in the presence of penicillinase. The data of the study showed that acid hydrolysis of the amidine analogues of penicillins resulted in cleavage of the beta-lactame cycle and formation of the respective penicillanic acids. In the alkaline medium the secondary amine (hexamethylenimine, dimethylamine, morpholine) was cleaved from the antibiotic side chain and the resulting N-formyl-6-aminopenicillanic acid was further cleaved up to peniciec acid. The beta-lactame cycle of the antibiotics was cleaved under the effect of penicillinase and the resulting penicilloinic acids degraded into peniciec acid, N-formylpeniciec acid and secondary amines. In the nutral solution the antibiotics were transformed into N-formyl-6-aminopenicillanic acid and penicilloinic acids at the first stage of the hydrolysis followed by their further degradation with formation of N-formylpeniciec acid, peniciec acid and secondary amines.

Amidines↗

PubMedDate not supplied

[Effect of amidine and guanidine derivatives on thrombocyte aggregation].

The capacity of 25 different amidines, guanidines and biguanidines to suppress the thrombocytes aggregation, induced by adenosinodiphosphate, was studied. Good prospects of a search for antiaggregation agents in this series of compounds are shown. N-benzyl-N1-propionylguanidine was found to reduce by more than 4 times the induced adhesiveness of the blood platelets.

Amidines↗

PubMed1977

[Stability of the amidine analogs of penicillin and deacetoxycephalosporin to the penicillinase of Bacillus licheniformis 749/c].

Fermentative hydrolysis of 3 derivatives of 6-beta-amidinopenicillanic acid and I derivative of 7-beta-amidinodeacetoxycephalosporanic acid by penicillinase produced by Bacillus licheniformis 749/c was studied. It was found that 6-beta-[(hexahydro-IH-azepin-I-yl) methyleneamino] penicillanic acid, 6-beta-(N1 N-dimethylformamidino-N1) penicillanic acid and 6-beta [(morpholin-I-yl) methylenemino] penicillanic acid were hydrolyzed by the enzyme 50, 70, and 160 times respectively slower than benzylpenicillin. 7-beta-[(Hexahydro-IH-azepin-I-yl)' methylenemino] deacetoxycephalosporanic acid proved to be at least 10 times more stable to the effect of penicillinase than methicillin. In addition unlike the amidine analogues of penicillin the above compound had an inhibitory effect on penicillinase produced by Bacillus licheniformis 749/c.

Amidines↗

PubMedDate not supplied

Epileptogenic activity in the amygdala is not affected by the amidine steroid, R 5135.

The synthetic steroid amidine 3-alpha-hydroxy-16-imino-5-beta-17aza androstan-11-one (R 5135) is known to elicit long-lasting spiking in the cortex in the presence of neocortical damage. R 5135 administered to amygdaloid-kindled and naive rats resulted in regular, high-amplitude spiking in the cortex but only occasionally elicited small-amplitude spikes in the amygdala (AMY) and hippocampus (HPC). Interictal spikes from the AMY of kindled rats were not synchronized with cortical spikes induced by the steroid. Given that R 5135 is known to be a GABAA receptor antagonist, these findings suggest that GABAA receptors in AMY and HPC may have lower affinity for 3 alpha-hydroxysteroids.

Amygdala↗