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PubMedDate not supplied

[The effect of the new nootropic dipeptide GVS-111 in different functional disorders of the escape reaction].

The authors studied the effect of a new nootropic agent with anxiolytic properties GVS-111 (ethyl ether N-phenylacetyl-L-prolylglycine) on formation of the avoidance reaction (AR) in rats and its functional disorders which were induced by two methods. In one case the stereotype of the relations between the stimulus, reaction and its consequence which developed during the experiment were urgently disturbed: the change of the animal to the other half of the chamber in response to a conditioned stimulus did not lead to its cutting off and prevention of the electropain stimulation for three successive combinations (AR error). In another case the spatial stereotype of the experiment was altered by changing the place of the opening through which the animal avoided the stimulus (spatial remodeling). Intraperitoneal injection of GVS-111 (0.1 mg/kg/day) improved the learning, but the effect differed from experiment to experiment. Along with this, the dipeptide prevented AR disturbance during the error and quickened restoration of the habit in spatial remodeling. It was shown earlier that AR disorders during an error are prevented by anxiolytics and nootropic agents but during spatial remodeling only by nootropic agents. It may be assumed that the positive effect of GSV-111 on AR in functional disorders is due to its nootropic effect.

Acoustic Stimulation↗
PubMed1984

Experimental uveitis. Elicited by peptidoglycan-polysaccharide complexes, lipopolysaccharide, and muramyl dipeptide.

Uveitis could be a reaction to bacterial debris disseminated to the eye from extraocular sites of infection. In this study, we relate the composition of several bacterial components to their inflammatory properties in the eye. Groups of rabbits were injected intravitreously with peptidoglycan-polysaccharide (PG-PS) complexes isolated from group A streptococci, Escherichia coli lipopolysaccharide (LPS), or synthetic muramyl dipeptide (MDP). The lipid A region of LPS and the glycan backbone of PG are chemical analogues; MDP is the minimal biologically active subunit of PG. All of these molecules elicited uveitis as observed both clinically and histologically. The MDP elicited an acute inflammation characterized by a heterophil and monocyte infiltrate that subsided within 16 days. The PG-PS and LPS elicited chronic inflammation characterized by mononuclear and lymphocyte infiltration and severe necrosis of the retina.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1988

Effects of muramyl dipeptide and core body temperature on peritoneal bacterial clearance.

To examine the interaction between muramyl dipeptide (MDP) and core body temperature in murine peritonitis, 120 Sprague-Dawley rats were randomized to receive either 0, 1, or 4 micrograms/g body weight of MDP. Twenty-four hours later a sublethal intraperitoneal inoculation of Escherichia coli was given after core body temperature regulation at 32 degrees C to 40 degrees C, which was maintained for 30 minutes. Killing of the rats at 1, 3, or 6 hours later allowed evaluation of peritoneal white blood cell and bacterial counts. Results demonstrated that MDP (independent of core body temperature) caused an increased peritoneal white blood cell response at one and six hours and an increased peritoneal bacterial clearance at three hours. Increasing core body temperature adversely affected peritoneal bacterial clearance. High-dose MDP was clearly significant in acceleration of peritoneal bacterial clearance. No interaction between MDP and core body temperature was seen.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1998

Large acceleration of alpha-chymotrypsin-catalyzed dipeptide formation by 18-crown-6 in organic solvents

The effects of 18-crown-6 on the synthesis of peptides catalyzed by alpha-chymotrypsin are reported. Lyophilization of the enzyme in the presence of 50 equivalents of 18-crown-6 results in a 425-fold enhanced activity when the reaction between the 2-chloroethylester of N-acetyl-L-phenylalanine and L-phenylalaninamide is carried out in acetonitrile. Addition of crown ether renders the dipeptide synthesis in nonaqueous solvents catalyzed by alpha-chymotrypsin possible on a preparative scale. The acceleration is observed in different solvents and for various peptide precursors. Copyright 1998 John Wiley & Sons, Inc.

Journal Article↗
PubMedDate not supplied

Simulated dipeptide recognition by vancomycin.

The antimicrobial activity of vancomycin and related glycopeptide antibiotics is due to stereospecific recognition of polypeptide components in bacterial cell walls. To better understand how these antibiotics recognize polypeptide determinants, we have developed dynamic models of the complexes formed by the vancomycin aglycon and two different dipeptide ligands, Ac-D-ala-D-ala and Ac-D-ala-gly. Molecular dynamics simulations of the two complexes, initially conditioned with distance constraints derived from two-dimensional nuclear magnetic resonance (NMR) studies, are conformationally stable and propagate in a manner consistent with the NMR-derived constraints after the constraints are removed. Free energy calculations accurately predict the relative binding affinity of these two complexes and help validate the simulation models for detailed structural analysis. Although the two ligands adopt similar conformations when bound to the antibiotic, there are clear differences in the configuration of intermolecular hydrogen bonds, the overall shape of the antibiotic, and other structural features of the two complexes. This analysis illustrates how complex structural and dynamic factors interrelate and contribute to differences in binding affinity.

Anti-Bacterial Agents↗
PubMedDate not supplied

Conformational analysis of the dipeptide taste ligand L-aspartyl-D-2-aminobutyric acid-(S)-alpha-ethylbenzylamide and its analogues by NMR spectroscopy, computer simulations and X-ray diffraction studies.

A dipeptide taste ligand L-aspartyl-D-2-aminobutyric acid-(S)-alpha-ethylbenzylamide was found to be about 2000 times more potent than sucrose. To investigate the molecular basis of its potent sweet taste, we carried out conformational analysis of this molecular and several related analogues by NMR spectroscopy, computer simulations and X-ray crystallographic studies. The results of the studies support our earlier model that an L-shape molecular array is essential for eliciting sweet taste. In addition, we have identified an aromatic group located between the stem and the base of the L-shape, which is responsible for enhancement of sweetness potency. In this study, we also assessed the optimal size of the essential hydrophobic group (X) and the effects of the chirality of the second residue toward taste.

Aminobutyrates↗
PubMed1992

Synthesis and inhibitory activities against aminopeptidase B and enkephalin-degrading enzymes of ketomethylene dipeptide analogues of arphamenines.

Three ketomethylene pseudodideptide analogues [(S)Lys psi(COCH2)(R and S)Phe (14 or 15 and 15 or 14) and (S)Lys psi(COCH2)(xi Trp (19)] of natural arphamenine A [(S)Arg psi(COCH2(R,S)Phe (1)] were easily prepared by a route involving two successive main reactions: a malonic ester alkylation with Z-protected lysine iodomethyl ketone and the introduction of a benzyl or (indol-3-yl)methyl moiety in position 2 of the resulting 4-ketodiester. The isomer of 1 with reversed sequence, (S)Phe psi(COCH2)(R,S)Arg (22) was synthesized by guanidylation and subsequent deprotection of Z-(S)Phe psi(COCH2)(R,S)Orn. The inhibitory effects of compounds 14, 15, 19, and 22, and the related ketomethylene dipeptides (S)Ala psi(COCH2)(R,S)Phe (3), (S)Phe psi(COCH2)(R,S)X [X = Ala (4), Orn (5)] and (S)Trp psi(COCH2)(R,S)Y [Y = Orn (6), Lys (7), Arg (8)] on aminopeptidase B (AP-B), and enkephalin-degrading enzymes [aminopeptidase N (APN) and neutral endopeptidase (NEP)] were compared with that of the model compound 1.

Aminopeptidases↗
PubMed1984

Muramyl dipeptide increases tolerance to shock and bacterial challenge in mice.

We measured the phagocytic capacity of the reticulo-endothelial system by assay of the clearance of colloidal carbon from the blood stream in both normal mice and mice in which shock had been induced by intraperitoneal injection of hypertonic glucose. The group of shocked mice was further subdivided into those pretreated with the immunoadjuvant, muramyl dipeptide (MDP), and those given placebo. Shock reduced reticulo-endothelial phagocytosis (P less than 0.01), whereas pretreatment of shocked mice with MDP led to a hyperphagocytic state (P less than 0.01). In a second series of experiments we subjected shocked mice, pretreated with MDP or placebo, to a virulent Klebsiella pneumoniae infection. MDP significantly improved survival (P less than 0.01).

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMedDate not supplied

A sensitive and specific high performance liquid chromatographic assay for imidazole dipeptides and 3-methylhistidine in human muscle biopsies, serum and urine.

A sensitive and specific high performance liquid chromatographic method is described for measuring imidazole dipeptides and 3-methylhistidine in human muscle biopsies, serum and urine. Muscle extract, serum or urine was reacted with o-phthaldialdehyde and the derivatives were separated by reversed phase chromatography with column switching and fluorescence detection.

Anserine↗
PubMed2004

Determination of binding constants of cyclodextrin inclusion complexes with amino acids and dipeptides by potentiometric titration.

Cyclodextrins are well known for their ability to separate enantiomers of drugs, natural products, and other chiral substances using HPLC, GC, or CE. The resolution of the enantiomers is due to the formation of diastereomeric complexes between the cyclodextrin and the pairs of enantiomers. The aim of this study was to determine the binding constants of the complexes between alpha- and beta-cyclodextrin and the enantiomers of a series of aliphatic and aromatic amino acids, and dipeptides, using a potentiometric titration method. The results of this method are compared to other methods, and correlated to findings in cyclodextrin-modified capillary electrophoresis and possible complex structures. Potentiometric titration was found to be an appropriate tool to determine the binding constants of cyclodextrin inclusion complexes.

Amino Acids↗
PubMed1978

The macrophage, target cell of the synthetic adjuvant muramyl dipeptide.

The mechanism of adjuvant activity of the synthetic glycopeptide N-acetylmuramul-L-alanyl-D-isoglutamine or muramyl dipeptide (MDP) was studied using in vitro plaque-forming cell (PFC) response to sheep erythrocytes (SRBC). Addition of MDP to DBA/2 mouse spleen cell cultures resulted regularly in a 2 to 3-fold increase of PFC numbers/10(6) recovered cells (p less than 0.01). Supernates (SPN) from MDP-stimulated cultures added to standard spleen cell + SRBC cultures brought about even more important increases of PFC numbers (p less than 0.01 to p less than 0.001). SPN from cultures supplemented with MDP alone (without SRBC) were more active than those of cell + MDP + SRBC cultures, and SPN removed on day 3 of culture were more active than those of day 5. This activity of SPN was maintained accross an H-2 histocompatibility barrier. Although pretreatment of spleen cells with anti-theta antigen serum entirely suppressed the anti-SRBC PFC response in spite of the presence of MDP, SPN from these cultures were as active as SPN from normal spleen cell MDP-stimulated cultures. In contrast, pretreatment of spleen cells with specific rabbit anti-mouse macrophage serum entirely suppressed both anti-SRBC response and SPN activity. It was concluded that the target cell for MDP is the macrophage which releases factors ultimately acting on B cells through T cell mediation.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1982

Demonstration of muramyl dipeptide (MDP)-induced T suppressor cells responsible for MDP immunosuppressive activity.

Muramyl dipeptide (MDP), a synthetic immunostimulant, has been previously shown to increase or decrease the humoral and cellular immune responses, depending upon the experimental conditions used. In the present study we have investigated the mechanisms of MDP-induced immunosuppression. After repeated injections of high dosages of MDP in vivo, both adherent and B cell-enriched cell populations from MDP-treated mice were able to collaborate with normal complementary populations. In contrast, T cell-enriched populations exhibited suppressive activity which could be removed by treatment with anti-Thy-1.2 antiserum and complement. These results clearly indicate that MDP-induced immunosuppression is mediated by T cells.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

Correlation between ribosylation of pertussis toxin substrates and inhibition of peptidoglycan-, muramyl dipeptide- and lipopolysaccharide-induced mitogenic stimulation in B lymphocytes.

Selective inhibition by pertussis toxin (PT) of mitogenic activation of mouse B lymphocytes by bacterial mitogens (peptidoglycan and lipopolysaccharide) and muramyl dipeptide (a synthetic analog of peptidoglycan fragment) was demonstrated. Mitogenic activation of B cells by protein kinase C activators and ionomycin was insensitive to PT. Also PT did not inhibit peptidoglycan- and lipopolysaccharide-induced differentiation of B cells into Ig-secreting cells, when it was added to the cultures after the proliferative stage of the response. B lymphocyte membranes contained two major PT substrates (40 and 41 kDa). The extent of PT-mediated ADP ribosylation of these substrates correlated with the degree of PT-mediated inhibition of mitogenic stimulation of B cells. B cell stimulation by all mitogens tested was not inhibited by cholera toxin at nontoxic concentrations that are known to cause maximal increase in cAMP in B cells. Since the only known substrates for PT-mediated ADP ribosylation in mammalian cells are the alpha subunits of some G proteins, our data suggest that G proteins are present in B cell membranes and that they are involved in B cell activation induced by bacterial mitogens.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1998

The modified dipeptide, enalapril, an angiotensin-converting enzyme inhibitor, is transported by the rat liver organic anion transport protein.

Oatp1, the organic anion transport polypeptide, is an integral membrane protein cloned from rat liver that mediates the uptake of various organic anions such as bromosulfophthalein (BSP) and taurocholate (TCA). Recent studies by others revealed that the thrombin inhibitor, CRC 220, a modified dipeptide, was transported by oatp1. The present study was designed to examine whether another modified peptide, enalapril, an angiotensin-converting enzyme inhibitor, was also a substrate. Transport was studied with enalapril (1 to 800 micromol/L, with [3H]enalapril) in a HeLa cell line stably transfected with oatp1-cDNA under the regulation of a Zn2+-inducible promoter. Noninduced transfected cells (without zinc) that did not express oatp1 failed to take up enalapril. In contrast, cells expressing oatp1 transported enalapril, estrone sulfate (E1S), taurolithocholic acid sulfate (TLCAS), and the glutathione conjugate of BSP (BSPGSH). Uptake of enalapril by oatp1 at 37 degreesC was substantially higher than that at 4 degreesC. The rate at 37 degreesC (uptake rates for induced - noninduced, transfected cells) was linear over 5 minutes and was concentration-dependent, characterized by a Km of 214 +/- 67 micromol/L and a Vmax of 0.51 +/- 0.15 nmol/min/mg protein. Enalapril uptake was inhibited competitively by BSP (at 1, 5, 10, and 50 micromol/L) and TCA (at 5, 25, and 100 micromol/L) with inhibition constants (Ki) of 2 and 32 micromol/L, respectively. The metabolite enalaprilat was, however, not transported by oatp1. That oatp1 is not a general transporter of anionic compounds was further shown by the lack of transport of harmol sulfate, benzoate, and hippurate. These observations attest to the role of oatp1 as a specific transporter for at least two classes of pharmacologically important peptides.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Changes in rabbit febrile responses to muramyl dipeptide (MDP) after coupling to a synthetic carrier.

Muramyl dipeptide (MDP) is a small molecular weight synthetic glycopeptide (less than 500), which has been shown to be an immunoadjuvant, and to induce a biphasic febrile response in the rabbit--probably via the release of endogenous pyrogen--accompanied by a marked leukopenia. Macromolecularization by coupling to a synthetic carrier (MW approximately or equal to 60,000) potentiates the immunostimulant properties of MDP but also its pyrogenicity. The present study demonstrates that such a conjugate induced the release of endogenous pyrogen in vivo and in vitro at lower dosage levels than free MDP. Further experiments showed that there existed several differences between free and conjugated MDP. Thus, after intravenous administration of the conjugate, the fever pattern was monophasic with a prompt defervescence and not accompanied by leukopenia at dosage levels inducing similar increase in body temperature. In addition, when fever was recorded after intracerebroventricular administration, the increase in sensitivity was much greater in the case of free MDP than of MDP-A--L.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

Preparation for hapten help by glucan, muramyl dipeptide, and its L-ala-Glycerol-mycolate derivative.

Previously, we reported that one of the factors that determines whether or not an animal will be prepared for hapten help after priming is the type of adjuvant used. The present work was undertaken, therefore, to determine which of a diverse variety of adjuvants or biological response modifiers would be effective. They included Freund's complete (CFA) and incomplete (FICA) adjuvants, particulate glucan, muramyl dipeptide (MDP), and its L-ala-glycerol-mycolate derivative. Help by the azobenzenearsonate (ABA) hapten was measured as the augmentation of the anti-bovine gamma-globulin (BGG) plaque-forming cell (PFC) response to ABA-BGG of mice that had been hapten-primed with ABA conjugated to ovalbumin (OVA). The results showed that FICA was ineffective. MDP was effective but only if administered with FICA during hapten-priming. MDP-L-ala-glycerol-mycolate was effective without any adjuvant but only within a narrow dose range. Particulate glucan was as effective as CFA in preparing mice for hapten help. As the macrophage is the primary cellular target of those biological response modifiers that were effective, we conclude that it plays an important role in the cellular interaction involved in the mediation of hapten help.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1987

Preferential loss of DNA polymerase alpha following suppression of replicative DNA synthesis of guinea pig macrophages by the immunostimulants muramyl dipeptide or lipopolysaccharide.

Oil-induced guinea pig peritoneal exudate macrophages were found to incorporate 3H-thymidine into trichloroacetic acid-insoluble fraction. In pulse-labeling experiments, the incorporated 3H-thymidine was detected in short fragments of DNA, which corresponded to the Okazaki fragments. These results indicate that the observed thymidine incorporation is due to nuclear DNA replication but not DNA repair. The observed DNA synthesis of the macrophages was remarkably suppressed when the cells were cultured in a presence of muramyl dipeptide (MDP) or bacterial lipopolysaccharide (LPS). The significant decrease of DNA polymerase alpha activity was found in the cells treated with MDP or LPS. In contrast, the activity of polymerase beta was not at all affected by the same treatment.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1988

Decrease in pyrogenicity of muramyl dipeptide after coupling with luteinizing hormone-releasing hormone.

Muramyl dipeptide (MDP) and its adjuvant active derivative lysine-MDP (Lys-MDP) have been demonstrated to be pyrogenic and to induce endogenous pyrogen (EP) production in vivo and in vitro. It has recently been shown that immunologic castration can be achieved in mice by immunization with luteinizing hormone-releasing hormone (LHRH) directly conjugated by carbodiimide to Lys-MDP, termed LHRH-Lys-MDP (cdi), or with a linear monomeric MDP-linked molecule obtained by total synthesis, termed LHRH-Lys-MDP (s). These preparations were tested in the rabbit for their capacity to induce fever and were found to be devoid of pyrogenicity at dosage levels of Lys-MDP that induced fever. This decrease of pyrogenicity of Lys-MDP after coupling to LHRH seems to be related to the structure of the conjugate because the derivative LHRH-LysNH2-MDP exhibited the same pyrogenic activity as the free glycopeptide. Surprisingly, nonpyrogenic LHRH-Lys-MDP induced production of EP and interleukin-1 (IL-1) in vitro and increased in vivo modifications of metal levels attributed to the action of IL-1. Moreover, LHRH-Lys-MDP reduced the pyrogenic effect of an exogenous dose of EP.

Acetylmuramyl-Alanyl-Isoglutamine↗