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PubMed1988

Formation of 2-guanidinoethanol by a transamidination reaction from arginine and ethanolamine by the rat kidney and pancreas.

The formation of 2-guanidinoethanol (GEt) from L-arginine (Arg) and ethanolamine (EA) was studied using rat kidney homogenates. Maximum GEt formation was observed between pH 8.7 and 9.1, and the enzyme catalyzing the GEt synthesis was stable between pH 5.6 and 9.1. The rate of GEt formation from Arg and EA by rat kidney homogenates obeyed simple Michaelis-Menten type kinetics. L-Ornithine and glycine inhibited GEt formation by rat kidneys. Both of them inhibited GEt formation in a linear mixed-type inhibitory manner when Arg concentrations were varied at a fixed concentration of EA, while they showed competitive inhibition when EA concentrations were varied at a fixed concentration of Arg. L-Canavanine and guanidinoacetic acid as well as Arg acted as an amidine donor for GEt formation, but L-homoarginine, 3-guanidinopropionic acid and 4-guanidinobutyric acid did not. GEt synthesis was also observed in the rat pancreas. It had almost half of the activity of rat kidney to form GEt. This ratio of kidney to pancreas was approximately equal to that of L-arginine:glycine amidinotransferase (transamidinase, EC 2.1.4.1) in kidney and pancreas. These results suggest that GEt may be synthesized from Arg and EA by a transamidinase catalyzing reaction.

Amidinotransferases↗
PubMed1985

Comparison of the action of types A and F botulinum toxin at the rat neuromuscular junction.

Blockade of neuromuscular transmission was produced in the lower hind limb of the rat by local injection of either type A or type F botulinum toxin (BoTx). At 1, 3, 7, and 10 days after injection, the extensor digitorum longus (edl) nerve-muscle preparation was excised and analyzed for alterations in muscle mechanical properties or spontaneous and nerve stimulus-evoked quantal transmitter release. Muscles receiving type A toxin were paralyzed up to and including 7 days after injection. Muscles treated with type F toxin, although completely paralyzed at 1 and 3 days after injection, twitched in response to nerve stimulation by 7 days. Both toxins induced a marked decrease in the frequency of miniature end-plate potentials, but type A did so to a greater extent. Between 1 and 3 days after toxin injection nerve impulse-evoked transmitter release was reduced in both type A- and type F-treated muscles. Evoked release was temperature sensitive in type A-treated muscles but not in those treated with type F. 3,4-Diaminopyridine (3,4-DAP), a compound which increases nerve-evoked transmitter release by increasing Ca2+ influx, was more effective in reversing the paralysis in type A than in type F-treated muscles. 3,4-DAP induced asynchronous end-plate potentials in response to nerve stimulation in type F-paralyzed muscles, but not in muscles treated with type A. Amidination of the amino groups (presumably lysine) on the toxin by treatment with ethylacetimidate increased the potency and efficacy of only type F BoTx. The results show that type F BoTx differs from type A, mainly by its lower potency, efficacy, shorter duration of action, and by being less effectively antagonized by 3,4-DAP.

4-Aminopyridine↗
PubMed1990

Effects of chemical modifications of Pa-11, a phospholipase A2 from the venom of Australian king brown snake (Pseudechis australis), on its biological activities.

Pa-11, a phospholipase A2 isolated from the venom of an Australian elapid snake Pseudechis australis, was chemically modified and its enzymic, neuromuscular and lethal activities were studied. Carboxymethylation of Met-8 gave a derivative with 2% of the enzymic activity and less than 3% of the lethal activity of native Pa-11; it had about 5% of the original ability to block directly and indirectly stimulated mouse phrenic nerve-hemidiaphragm preparations. Nitrophenylsulfenylation of tryptophanyl residues at positions 31 and 69 caused loss of all activities. Amidination of all 14 lysyl residues gave a derivative with 41% and 16% of the enzymic and lethal activities, respectively, but with less than 5% of the original neuromuscular blocking activity. Mono-carbamoylation of lysyl residues at positions 58, 63, 81 and 85 was achieved. The most abundant derivative, 58-carbamoyl-lysine Pa-11 was enzymically 130% and lethally 100% as active as native Pa-11, but it had only about 20% of the native's neuromuscular activity in vitro. 63-Carbamoyl-lysine Pa-11 had 10% of the enzymic and 20% of the lethal activities, respectively; however, it retained at least 50% of its ability to block neuromuscular transmission in vitro, while losing most of its activity to block directly stimulated muscle contractions. 81- and 85-Carbamoyl derivatives have the same enzymic and lethal activities as the original protein, but the 85 derivative had less than 10% of the native neuromuscular activity. Hence, modifications of lysine residues at positions 58, 63 and 85 seem to be particularly significant in altering the neuromuscular, but not enzymic, activity of Pa-11, perhaps by altering the ability of the toxin to bind to its target on nerve and muscle membranes. Modification at position 63 appeared to lead to a dissociation of effects on neuromuscular transmission and directly on muscle cells.

Amino Acid Sequence↗
PubMed1992

Characterisation of melarsen-resistant Trypanosoma brucei brucei with respect to cross-resistance to other drugs and trypanothione metabolism.

An arsenical resistant cloned line of Trypanosoma brucei brucei was derived from a parent sensitive clone by repeated selection in vivo with the pentavalent melaminophenyl arsenical, sodium melarsen. The melarsen-resistant line was tested in vivo in mice against a range of trypanocidal compounds and found to be cross-resistant to the trivalent arsenicals, melarsen oxide, melarsoprol and trimelarsen (33, 67 and 122-fold, respectively). A similar pattern of cross-resistance was found in vitro using a spectrophotometric lysis assay (greater than 200-fold resistance to melarsen oxide and greater than 20-fold resistance to both trimelarsen and melarsoprol). Both lines were equally sensitive to lysis by the lipophilic analogue phenylarsine oxide in vitro, suggesting that the melamine moiety is involved in the resistance mechanism. Although trypanothione has been reported to be the primary target for trivalent arsenical drugs [1], levels of trypanothione and glutathione were not significantly different between the resistant and sensitive lines. Statistically significant differences were found in the levels of trypanothione reductase (50% lower in the resistant clone) and dihydrolipoamide dehydrogenase (38% higher in the resistant clone). However, the Km for trypanothione disulphide, the Ki for the competitive inhibitor Mel T (the melarsen oxide adduct with trypanothione) and the pseudo-first order inactivation rates with melarsen oxide were the same for trypanothione reductase purified from both clones. The melarsen-resistant line also showed varying degrees of cross-resistance to the diamidines: stilbamidine (38-fold), berenil (31.5-fold), propamidine (5.7-fold) and pentamidine (1.5-fold). Cross-resistance correlates with the maximum interatomic distance between the amidine groups of these drugs and suggests that the diamidines and melaminophenyl arsenicals are recognised by the same transport system.

Animals↗
PubMed1990

Chemical modification of erythropoietin: an increase in in vitro activity by guanidination.

Human recombinant erythropoietin (rHuEPO) was chemically modified with several group-specific reagents in order to study the role of each kind of amino-acid residue in its biological activity. Guanidination of the amino groups of the lysine residues yielded derivatives that showed higher activities in vitro than native rHuEPO, whereas amidination had no effect on the activity. By contrast, modification of the positive charges of the lysine residues to neutral or negative charges, such as in carbamylation, trinitrophenylation, acetylation or succinylation, caused a significant loss of rHuEPO activity. Chemical modification of other amino-acid residues, such as arginine and tyrosine residues or carboxyl groups, also led to loss of activity.

Arginine↗
PubMed1983

On the possible significance of the transamidination reaction in evolution.

The origin of the various muscle phosphagens during evolution is considered in the context of the need to conserve ornithine for the synthesis of proline for connective tissue necessary for structural strength and flexibility and/or a complicated musculature. In each phosphagen, arginine is known to have contributed its amidine moiety thus maintaining the function of the phosphagen and setting free the proline precursor ornithine. Tissues from an earthworm, a starfish and a sea-squirt have been found to contain the enzymes arginase, ornithine aminotransferase and pyrroline-5-carboxylate reductase which are necessary to convert arginine to proline. For each of the animals studied analysis for the relevant free amino acids and for the characteristic amino acids (Pro, Oh-Pro, Oh-Lys, Gly) of collagen are presented. The amino acid composition of the diet of the sea-squirt Pyura stolonifera and of the starfish Coscinasterias calamaria is presented along with the level of the phosphagen kinases of the animals studied. The significance of the experimental results is discussed in connection with the importance of the transamidination reaction.

Amino Acids↗
PubMed1985

[Not Available].

Changes in the ultraviolet absorption spectra with pH in aqueous solution were used to determine the pKA values of amidines. A new mathematical procedure was used to study sparingly soluble compounds. In this technique, all the experimental data are used to solve for the absorbance of the insoluble basic species and for the pKA value by a 'complex method' of optimization, which is more general than the classical least-squares method. A relationship between a double bond vibration frequency and the acidity constants of these compounds has been demonstrated.

English Abstract↗
PubMed1992

Complex interactions between the steroid derivative RU 5135 and the GABAA-receptor complex.

The modulation of [35S]t-butylbicyclophosporothionate ([35S]TBPS) binding was used to evaluate the actions of the steroid derivative RU 5135 at the gamma-aminobutyric acidA (GABAA) receptor complex. The inhibition of [35S]TBPS binding by GABA in the presence of various concentrations of RU 5135 was consistent with the hypothesis that RU 5135 is a competitive antagonist at the GABAA receptor. Despite common structural features (i.e., 3 alpha-hydroxylated, 5 beta-reduced A ring) with GABAA receptor-active neurosteroids, RU 5135 did not appear to be competitive at the putative steroid site on the GABAA receptor-active, as demonstrated by Schild analysis of 5 alpha-pregnane-3 alpha-ol-20-one (3 alpha,5 alpha-P) modulation of [35S]TBPS binding in the presence of different concentrations of RU 5135. On the other hand, the reduced potency of 3 alpha,5 alpha-P as an inhibitor of [35S]TBPS binding in the presence of RU 5135, as well as blockade of 5 alpha-pregnane-3 alpha-20 alpha-diol (5 alpha-pregnanediol) inhibition of [35S]TBPS binding by RU 5135 provide further support for the GABAA receptor antagonist properties of RU 5135. Moreover, this amidine steroid was able to partially inhibit [35S]TBPS binding independent of GABA with nanomolar potency; yet the mechanism by which this occurs remains to be determined.

Androstanes↗
PubMed2005

Immobilization of an anticoagulant benzamidine derivative: effect of spacer arms and carrier hydrophobicity on thrombin binding.

Prevention of blood coagulation is very often a prerequisite for successful medical devices. For that purpose, passivation of the key coagulation enzyme thrombin through the derivatization of the material's surface with an amidine-based molecule has been found to be promising. To further enhance the efficiency of this approach, thin layers of maleic anhydride copolymers offering different physico-chemical characteristics were tethered with carboxyl terminated polyethylene glycol to covalently immobilize a benzamidine-type derivative. The free carboxyl surface groups produced by the attachment of polyethylene glycol (PEG) were quantified by Ag(+) labeling and subsequent XPS detection. The film thickness as well as the carboxyl group content were found to be clearly dependent on the copolymer hydrophobicity and the nature of the PEG molecule. For the assessment of the anchorage of the thrombin to the benzamidine-derivative functionalized surfaces, the substrates were immersed in a buffered thrombin solution and the enzyme adsorption was studied using immunostaining/confocal laser scanning microscopy. Higher degrees of thrombin binding were observed for substrates configured with the hydrophilic compared to the more hydrophobic copolymer. Moreover, surface-bound spacers based on alpha,omega-heterobifunctional PEG amino acids (alphaAm,omegaAc-PEG) also enhanced the benzamidine surface density in comparison to homofunctional PEG diacids (alphaAc,omegaAc-PEG) because of a lower degree of carboxyl inactivation due to PEG 'bridging'. Altogether, the choice of copolymer coatings and the type of PEG spacers were demonstrated to enhance the efficiency of the thrombin scavenging by the covalently immobilized coagulation inhibitor.

Adsorption↗
PubMed2004

Phenyl substitution of furamidine markedly potentiates its anti-parasitic activity against Trypanosoma cruzi and Leishmania amazonensis.

Furamidine (DB75) and related unfused aromatic diamidines have proven useful for the treatment of parasitic infections. These compounds were primarily developed to combat infections by Pneumocystis carinii and African trypanosomes but they are also active against other parasites. Here we have investigated the in vitro effects of DB75 and its phenyl-substituted analog DB569 on two kinetoplastid haemoflagellates Trypanosomatidae: Trypanosoma cruzi and Leishmania (L) amazonensis. The phenyl-amidine compound DB569 has equivalent DNA binding properties compared to DB75 but it was selected on the basis of its distinct tumor cell distribution properties. We found that DB569 is significantly more potent than DB75 at reducing the proliferation of the parasites, using either isolated parasites in cultures or with cardiomyocyte and macrophage host cells. DB569 is effective towards the intracellular forms of T. cruzi (IC(50) in the low-micromolar range) and it exhibits trypanocidal dose-dependent effects against trypomastigote forms of T. cruzi parasites obtained from the Y strain and Dm28c clone, which belong to two different biodemes. Fluorescence microscopy experiments indicated that both diamidines were mostly localized in the nucleus of the mammalian host cells and within the nuclei and kinetoplast of the parasites. Electron microscopy studies showed that the treatment of the parasites with DB75 and DB569 induces important alterations of the parasite nucleus and kinetoplast, at sites where their DNA target is localized. Altogether, the data suggest that the phenyl-substituted furamidine analogue DB569 is a potential new candidate for the treatment of the Chagas' disease and Leishmaniasis.

Animals↗
PubMed2005

Synthesis and in vitro evaluation of a novel thiolated chitosan.

In order to achieve the same properties as chitosan-4-thio-butyl-amidine and to overcome at the same time its insufficient stability, the aim of this study was to evaluate the imidoester reaction of isopropyl-S-acetylthioacetimidate for the chemical modification of chitosan and to study the properties of the resulting chitosan-thioethylamidine (TEA) derivative. The thioalkylamidine substitute was introduced without the formation of N-substituted non-thiol products. The resulting conjugates exhibited 1.05+/-0.17% or 139.68+/-17.13 micromol immobilized free thiol groups per gram polymer and a total amount of reduced and oxidized thiol groups of 1.81+/-0.65% or 179.46+/-67.95 micromol/g polymer. By the immobilization of thiol groups mucoadhesion was strongly improved due to the formation of disulfide bonds with mucus glycoproteins. Chitosan-TEA was investigated regarding to its mucoadhesive properties via tensile studies and the rotating cylinder method. In tensile studies the total work of adhesion of chitosan-TEA was increased 3.3-fold in comparison to unmodified chitosan. Results from the rotating cylinder method showed an improvement ratio of 8.9 for chitosan-TEA compared with unmodified chitosan. In spite of the immobilization of thiol groups onto chitosan its swelling behavior in aqueous solutions was not significantly altered. Cumulative release studies out of matrix tablets comprising the chitosan-TEA and the model compound fluorescence labeled dextrane (FD(4)) demonstrated a controlled release over 3h with a trend toward a pseudo-zero-order kinetic. Because of these features the new chitosan thioamidine conjugate might represent a promising new polymeric excipient for various drug delivery systems.

Absorbable Implants↗
PubMed2006

Substituted thiophene-anthranilamides as potent inhibitors of human factor Xa.

A series of thiophene-containing non-amidine factor Xa inhibitors is described. Simple methyl-substituted thiophene analogs were relatively weak inhibitors. However, introduction of hydrophilic substituents at C-4 or C-5 of the thiophene afforded inhibitors with low nanomolar potency. Optimization of the thiophene substituent at C-4 afforded subnanomolar inhibitors with improved in vitro anticoagulant activity. Incorporating basic amine substituents on the thiophene increased hydrophilicity and improved anticoagulant activity. The pharmacokinetic profile of one inhibitor was evaluated in dogs, and the X-ray crystal structure of this compound bound to factor Xa provides insight into the observed SAR for binding to factor Xa.

Amides↗
PubMed2005

Combinatorial approaches towards the discovery of new tryptase inhibitors.

The synthesis and evaluation as tryptase inhibitors of a library of 2,5-diketopiperazine derivatives containing guanidine or amidine functional groups is reported. Among the compounds evaluated, derivatives 6{CG4-CG8} and 6{CG4-CG9} are the most active compounds and have marked selectivity towards tryptase in front of trypsin.

Combinatorial Chemistry Techniques↗
PubMed2005

Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 3: 8-Thiocarboxamido and 8-thioformamido derivatives of cyclazocine.

8-Position variants of cyclazocine have been made where the phenolic 8-OH was replaced by thioamide, amidine, guanidine, urea and thiourea groups. High affinity for opioid receptors was observed for the 8-CSNH2 and 8-NHCHS analogues indicating that these groups are isosteric with not only the 8-OH but with the previously synthesized 8-CONH2 and 8-NHCHO cyclazocine derivatives.

Cyclazocine↗
PubMed2005

Structure-based design and synthesis of pyrazinones containing novel P1 'side pocket' moieties as inhibitors of TF/VIIa.

We describe the structure-based design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors contain substituents meta to the P(1) amidine designed to explore additional interactions with the VIIa residues in the so-called 'S(1) side pocket'. A crystal structure of the designed inhibitors demonstrates the ability of the P(1) side pocket moiety to engage Lys192 and main chain of Gly216 via hydrogen bond interactions, thus, providing additional possibility for chemical modification to improve selectivity and/or physical properties of inhibitors.

Benzamidines↗
PubMed2006

Synthesis and biological evaluation of benzamides and benzamidines as selective inhibitors of VEGFR tyrosine kinases.

A series of benzamidines and benzamides was synthesized as selective inhibitors of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, and tested for inhibitory activity toward autophosphorylation by the enzyme assay. Selective inhibition of VEGFR-2 tyrosine kinase was observed in the salicylic amide 4e and the anthranilic amidine 5a, and their percent inhibitions of VEGFR-2 tyrosine kinase were 44-60% at a 10 microM concentration of compounds. The salicylic amide 4a showed inhibition of both VEGFR-1 and VEGFR-2 tyrosine kinases at a 10 microM concentration.

Animals↗