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At least 1,711 records · Page 95Linked to original sources
PubMed1997

Endoproteolysis of glucagon-like peptide (GLP)-1 (7-36) amide by ectopeptidases in RINm5F cells.

This study concerns whether the pancreatic beta cell expresses cell-surface ectopeptidases that are capable of proteolysis of peptide hormones and neuropeptides that modify glucose-dependent insulin release. These biochemical investigations of the RINm5F cell line found that these cells express ectopeptidases. We have characterized the limited endoproteolysis of GLP-1 (7-36) amide that occurs in the presence of RINm5F plasma membranes. The products and the sensitivity to specific peptidase inhibitors of the proteolysis is characteristic of neutral endopeptidase (NEP) 24.11. Vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase-activating peptide (PACAP), amylin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), and exendin-4 also undergo proteolysis in the presence of RIN cell membranes. NEP 24.11-activity in RIN cell membranes was confirmed using a specific fluorogenic assay, by histochemistry, and by comparison with the recombinant enzyme with respect to the kinetics of proteolysis of GLP-1 (7-36) amide and of a fluorogenic substrate. Specific fluorogenic assays revealed the presence of aminopeptidase N and the absence of aminopeptidase A and of dipeptidylpeptidase IV.

Amino Acid Sequence↗
PubMed1999

Alpha1-adrenergic regulation of peptidylglycine alpha-amidating monooxygenase gene expression in cultured rat cardiac myocytes: transcriptional studies and messenger ribonucleic acid stability.

Peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14.17.3) is a bifunctional protein containing two enzymes that act sequentially to catalyse the alpha-amidation of neuroendocrine peptides. Previous studies have demonstrated that alpha-adrenergic stimulation results in an increase in intracellular volume and protein content of cultured neonatal rat myocardial cells. The present study examined the regulated expression of PAM during alpha-adrenergic stimulation. Alpha1-adrenergic stimulation activates the expression and release of PAM from myocytes. Following phenylephrine treatment, myocardial cells displayed a several fold increase in PAM activity, and a 2-4-fold increase in the steady state levels of PAM mRNA. This effect of alpha-adrenergic stimulation was dependent on the concentration and duration of exposure to the agonist, and displayed alpha1-adrenergic receptor specificity. The transcription rate experiments indicated that these alpha-adrenergic effects were not due to increased PAM gene activity, suggesting that a post-transcriptional mechanism was involved. The most common mechanism of post-transcriptional regulation affects cytoplasmic mRNA stability. Cardiomyocytes cultures from atria and ventricles in the presence of 5,6 dichloro-1-beta ribofuranosyl benzamidazole (DRB) showed that phenylephrine treatment increased the half-life of PAM mRNA from 13 +/- 1 to 21 +/- 1 h in atrial cells and from 8 +/- 1 to 12 +/- 1 h in ventricle cells. Analysis of nuclear RNA with probes specific for PAM intron sequences shows that increased PAM expression after phenylephrine treatment was not due to intranuclear stabilisation of the primary transcript. Protein kinase C inhibitors H7 and GF109203x, completely blocked the phenylephrine stimulated PAM expression. These results suggest that alpha-adrenergic agonist induces PAM mRNA levels by increasing its stability in the cytoplasm. They indicate that PAM gene expression augments through a H7 and GF109203x sensitive pathway, involving the activation of protein kinase C.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2002

Influence of physico-chemical parameters of some barbituric acid derivatives on their retention on an amide embedded RP silica column.

Retention parameters of 45 different barbituric acid derivatives were determined on an amide embedded RP silica column (Discovery RP-AmideC16) using non-buffered water-acetonitrile eluent systems. Linear correlation were calculated between the logarithm of the capacity factor and the acetonitrile concentration in the eluent. To determine the retention behavior of barbituric acid derivatives, stepwise regression analysis (SRA) and principal component analysis (PCA) followed by two-dimensional nonlinear and modified nonlinear mapping was used. It can be concluded, the retention of barbituric acid derivatives are governed mainly by the steric parameters of the substituents. Principal component analysis indicated that the barbituric acid derivatives have mixed retention on this amide embedded RP silica column in water-acetonitrile eluent.

Barbiturates↗
PubMed2001

The hypnotic actions of the fatty acid amide, oleamide.

Oleamide is an endogenous fatty acid amide which can be synthesized de novo in the mammalian nervous system, and has been detected in human plasma. It accumulates in the CSF of rats after six hours of sleep deprivation and induces sleep in naive rats and mice. Inhibition of the primary catabolic enzyme of oleamide (fatty acid amide hydrolase) by trifluoromethyl-octadecenone reduces sleep latency and increases total sleep time when given centrally to rats and peripherally to mice. While the mechanism of action of oleamide is unclear, it has been demonstrated to increase the amplitude of currents gated by 5-HT2a, 5HT2c and GABAa receptors. Moreover, the action of oleamide most relevant to sleep induction involves, in part, cannabinergic pathways, as evidenced by the ability of the cannabinoid antagonist SR 141716 to inhibit the hypnotic actions of OA. Nonetheless, enhancement of cannabinergic function may not be the only mechanism by which OA alters sleep, as it can act synergistically with subthreshold doses of triazolam (0.125 microg) to reduce sleep latency. These findings raise the possibility that OA may be representative of a group of compounds which might be developed into clinically-used hypnotics, and are discussed in the context of fatty acid derivatives as modulators of neuronal function.

Animals↗
PubMed1999

Effect of large bowel fermentation on insulin, glucose, free fatty acids, and glucagon-like peptide 1 (7-36) amide in patients with coronary heart disease.

Insulin resistance syndrome has recently been described as a unifying hypothesis to explain the relationship between the many risk factors of coronary heart disease. Carbohydrate that is malabsorbed and fermented in the colon has been demonstrated to decrease insulin response to a glucose load and improve other risk factors associated with coronary heart disease, although the mechanism remains unclear. The object of the present study was to investigate whether this observation could be explained by the production of fermentation products induced by malabsorbed carbohydrate in the colon, or by stimulating the incretin glucagon-like peptide 1 (7-36) amide that is released from the large bowel. We used lactulose as a model for resistant starch carbohydrate. Ten insulin-resistant male volunteers, who had undergone previous coronary artery bypass grafting, volunteered to take part in the study and underwent 6 d of lactulose loading (15 g/d for 2 d and 30 g/d for 4 d). There was no significant change in insulin, glucose, free fatty acids, or glucagon-like peptide 1 (7-36) amide response to an oral glucose tolerance test following the lactulose despite a significant rise in breath hydrogen. Large bowel fermentation stimulated by lactulose appears to have no significant effect on insulin, glucose, free fatty acids, and glucagon-like peptide 1 (7-36) response in patients with coronary heart disease.

Aged↗
PubMed2001

The amide hydrogen of (-)-indolactam-V and benzolactam-V8's plays a critical role in protein kinase C binding and tumor-promoting activities.

To investigate the role of the amide hydrogen of (-)-indolactam-V (1) and benzolactam-V8's on protein kinase C (PKC) binding and tumor promotion, 8-decylbenzolactone-V8 (6), a new lactone analogue of 8-decylbenzolactam-V8 (4), was synthesized from 2-nitrophenylpyruvic acid (7) in 11 steps. The PKC binding ability and tumor-promoting activities in vitro of 6 were much lower than those of 1 and 4, suggesting that the amide hydrogen of 1 and benzolactam-V8's plays a critical role in tumor promotion. However, it is noteworthy that 6 showed significant selectivity in the PKC isozyme surrogate binding.

Antigens, Viral↗
PubMed2003

Arachidonylsulfonyl derivatives as cannabinoid CB1 receptor and fatty acid amide hydrolase inhibitors.

Arachidonylsulfonyl fluoride (3), reported here for the first time, is similar in potency to its known methyl arachidonylfluorophosphonate (2) analogue as an inhibitor of mouse brain fatty acid amide hydrolase activity (IC(50) 0.1 nM) and cannabinoid CB1 agonist [3H]CP 55,940 binding (IC(50) 304-530 nM). Interestingly, 3 is much more selective than 2 as an inhibitor for fatty acid amide hydrolase relative to acetylcholinesterase, butyrylcholinesterase and neuropathy target esterase. N-(2-Hydroxyethyl)arachidonylsulfonamide (4) is at least 2500-fold less potent than N-(2-hydroxyethyl)arachidonamide (anandamide) (1) at the CB1 agonist site.

Animals↗
PubMed2001

2-Alkynyl-8-aryladenines possessing an amide moiety: their synthesis and structure-activity relationships of effects on hepatic glucose production induced via agonism of the A(2B) adenosine receptor.

A series of 2-alkynyl-8-aryladenine derivatives bearing an amide moiety at the 9-position of adenine was synthesized. These analogues were evaluated for inhibitory activity on N-ethylcarboxamidoadenosine (NECA)-induced glucose production in primary cultured rat hepatocytes. The m-primary benzamide derivative 15f was the most potent compound (IC(50)=0.017 microM), being 15-fold more active than the corresponding 9-methyl derivative (1). Compound 15f showed 72- and 5.2-fold selectivity for human A(2B) receptor versus human A(1) and A(2A) receptors, respectively. Structure-activity relationship (SAR) studies of the synthesized compounds indicated that a three-carbon linker, fixed in the form of a benzene ring, between the adenine core and the amide moiety is important for both A(2B) antagonistic activity and selectivity. The IC(50) values in rat hepatocyte glucose assay correlated well with the IC(50) values in cAMP assay using Chinese hamster ovary cells stably transfected with human A(2B) receptors (r(2)=0.94). The A(1) and A(2A) affinities showed no correlation with the potency to inhibit NECA-induced glucose production. These results strongly support our previous conclusion that adenosine agonist-induced hepatic glucose production in rat hepatocytes is mediated through the A(2B) receptor.

Adenine↗
PubMed2003

Iso-lactam and reduced amide analogues of the peptidomimetic dopamine receptor modulator 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide.

An analogue of the highly potent gamma-lactam Pro-Leu-Gly-NH(2) peptidomimetic, 3(R)-[(2(S)-pyrrolidinylcarbonyl) amino]-2-oxo-1-pyrrolidineacetamide (2), 4(R)-[[2(S)-pyrrolidinylcarbonyl]amino]-2-oxo-1-pyrrolidineacetamide (3), in which the lactam carbonyl moiety has been placed in a different position with respect to the 3-amino group was synthesized. Also, a series of analogues of 2, compounds 4-6, were synthesized in which each of the amide bonds of 2 were systematically replaced with a reduced amide bond surrogate. The analogues were tested for their ability to enhance the binding of [3H]N-propylnorapomorphine to dopamine receptors in a functional in vitro assay utilizing bovine striatal membranes. Peptidomimetic 3 was shown to be more potent than 2, while 4 and 5 were significantly less effective than 2. Peptidomimetic 6 had a pharmacological profile similar to that of 2.

Animals↗
PubMed2002

Pm-149 DOTA bombesin analogs for potential radiotherapy. in vivo comparison with Sm-153 and Lu-177 labeled DO3A-amide-betaAla-BBN(7-14)NH(2).

Promethium-149 (149Pm) is one of only three radiolanthanides that can be prepared in no carrier added concentrations. This high specific activity radiolanthanide is thus suitable for targeting limited numbers of specific receptors found on many tumor cells. Promethium-149 is a moderate energy beta(-) emitter (1.07 MeV (95.9%)) with a half-life of 2.21 days. Pm-149 also emits a low abundance of an imageable gamma ray (286 keV (3%)) that may allow in vivo tracking of the therapeutic dose. The 149Pm and Sm complexes with the DO3A-amide chelator with zero and three carbon spacers to the bombesin peptide analog BBN(7-14)NH(2) were synthesized and characterized. The Sm complexes were synthesized for macroscopic characterization purposes (ESI-MS, in vitro cell binding) since no stable isotopes of Pm are known. The biological properties of the 149Pm, 153Sm and 177Lu-DO3A-amide-betaAla-BBN complexes were compared in normal mouse biodistribution studies.

Animals↗
PubMed1999

In vivo dynamic distribution of 131I-glucagon-like peptide-1 (7-36) amide in the rat studied by gamma camera.

The in vivo distribution of glucagon-like peptide-1 (7-36) amide (GLP-1) was studied in a rat model using radiolabeled GLP-1 (131I-GLP-1) depicted by a gamma-camera. The dynamic scan showed a rapid clearance from the blood circulation after an intravenous (i.v.) injection of 131I-GLP-1. After 10 min, the major part of the radioactivity was accumulated in the kidneys, whereas about 9% (of the blood value) was found in the brain. The pharmacokinetic study using 125I-GLP-1 demonstrated a rapid elimination from plasma, with a half-life of 3.3 +/- 0.6 min, a clearance of 117 +/- 15 mL/min, and a distribution volume of 557 +/- 61 mL. The elimination half-lives for the intact 125I-GLP-1 in lungs and kidneys were determined to 3.7 and 3.9 min, respectively. The metabolite GLP-1 (9-36) amide was followed in blood, lung, and kidney. All other organs assumed to contain low molecular weight fragments of GLP-1. The present study suggest that GLP-1 and/or its labeled metabolites cross the blood-brain barrier. Also the kidney plays an essential role in GLP-1 elimination after an i.v. administration, which can be of clinical interest especially in patients with kidney insufficiency who are treated with GLP-1.

Animals↗
PubMed2003

Evaluation of alkali and alkaline earth metal cation selectivities of lariat ether amides by electrospray ionization mass spectrometry.

Lariat ethers with pendant amide groups have shown promise as new ion sensors because of their selectivity towards particular metal ions. In this study we report alkali and alkaline earth metal binding selectivities of dibenzo-16-crown-5 and fifteen dibenzo-16-crown-5 lariat ether amides (LEAs) as determined by electrospray ionization mass spectrometry (ESI-MS). Additionally, the influence of the acid/base nature of the solution on metal cation selectivity is investigated. The validity of using ESI-MS for determination of selectivities is established by analogous experiments using hosts with known binding constants for the same metal cations and solvent systems. Collisionally activated dissociation (CAD) is used to evaluate the influence of the alkali metal cation binding on the fragmentation of the LEAs.

Journal Article↗
PubMed2003

Expression and characterization of human bifunctional peptidylglycine alpha-amidating monooxygenase.

We report the purification and characterization of human bifunctional peptidylglycine alpha-amidating monooxygenase (the bifunctional PAM) expressed in Chinese hamster ovary cells. PAM is in charge of the formation of the C-terminal amides of biologically active peptides. The bifunctional PAM possesses two catalytic domains in a single polypeptide, peptidylglycine alpha-hydroxylating monooxygenase (PHM, EC 1.14.17.3) and peptidylamidoglycolate lyase (PAL, EC 4.3.2.5). By introducing a stop codon at 835 Glu, we were able to eliminate the membrane-spanning domain in the C-terminal region and succeeded in purifying a soluble form of bifunctional PAM that was secreted into the medium. Through a three-step purification procedure, we obtained 0.3mg of the purified PAM, which showed a single band at 91 kDa on SDS-PAGE, from 1L of monolayer culture medium. Metals contained in the purified PAM were analyzed and chemical modifications were performed to gain insight into the mechanism of the PAL reaction. Inductively coupled plasma detected 0.62 mol of Zn(2+) and 1.25 mol of Cu(2+) per mol of bifunctional PAM. Further, the addition of 1mM EDTA reduced the PAL activity by about 50%, but the decreased activity was recovered by the addition of an excess amount of Zn(2+). In a series of chemical modifications, phenylglyoxal almost completely eliminated the PAL activity and diethyl pyrocarbonate suppressed activity by more than 70%. These findings implied that Arg and His residues might play crucial roles during catalysis.

Amidine-Lyases↗
PubMed2000

Competition in liver transport between chenodeoxycholic acid and ursodeoxycholic acid as a mechanism for ursodeoxycholic acid and its amidates' protection of liver damage induced by chenodeoxycholic acid.

BACKGROUND: Ursodeoxycholic acid has been widely used as a therapeutic agent in cholesterol gallstones and liver disease patients, but its mechanism of action is still under investigation. AIMS: The protective effect of ursodeoxycholic acid, both free, taurine and glycine conjugated, against hepatotoxic bile acids such as chenodeoxycholic acid and its taurine amidate was studied in bile fistula rats and compared with the cholic and taurocholic acid effect. METHODS: Tauroursodeoxycholic acid, glycine ursodeoxycholic acid, ursodeoxycholic acid, taurocholic acid and cholic acid were infused iv over 1 hour (8 micromol/min/kg) together with an equimolar dose of either taurochenodeoxycholic acid or chenodeoxycholc acid. Bile flow, total and individual bile acid and biliary lactate dehydrogenase and alkaline phosphatase enzymes were measured. RESULTS: Taurochenodeoxycholic acid and chenodeoxycholc acid caused cholestasis and liver damage associated with a decreased bile flow, total and individual bile acids secretion accompanied by a biliary leakage of lactate dehydrogenase and alkaline phosphatase enzymes. Tauroursodeoxycholic acid, glycine ursodeoxycholic acid, ursodeoxycholic acid and taurocholic acid, on the contrary, were choleretic, inducing an opposite effect on biliary parameters. Simultaneous infusion of taurochenodeoxycholic acid and the protective bile acid resulted in a functional and morphological improvement of the above parameters in the following order: glycine ursodeoxycholic acid > tauroursodeoxycholic acid > ursodeoxycholic acid followed by taurocholic acid; cholic acid was ineffective. CONCLUSIONS: The results show the protective effect of glycine ursodeoxycholic acid, ursodeoxycholic acid and tauroursodeoxycholic acid. This may be due to a facilitated transport of the toxic bile acid into bile; conjugation with taurine is less effective than glycine. Finally, the better protective effect of ursodeoxycholic acid and its amidates with respect to cholic acid and its taurine conjugated form seems to be related to their different lipophilicity and micellar forming capacity.

Alkaline Phosphatase↗
PubMedDate not supplied

Efficient calf thymus DNA condensation upon binding with novel bile acid polyamine amides.

Polyamine amides have been prepared from lithocholic and cholic acids (5beta-colanes) by acylation of tri-Boc-protected tetraamines spermine and thermine. These designed ligands for DNA are polyammonium ions at physiological pH. In NMR spectra, they display 14N-1H 1J = 51 Hz, 1:1:1 triplets, due to the symmetry of the R14NH(3)+ cations. The binding affinities of these conjugates for calf thymus DNA were determined using an ethidium bromide fluorescence quenching assay and compared with spermine and polylysine. DNA-binding affinities were dependent upon both salt concentration and the hydrophobicity or intermolecular bonding (facial effects) of the lipid moieties in these conjugates. Light scattering at 320 nm was used to determine DNA condensation and particle formation. The observed self-assembly phenomena are discussed with respect to DNA charge neutralization and DNA bending with loss of ethidium cation intercalation sites, ultimately leading to DNA condensation. These polyamine amides are models for lipoplex formation with respect to gene delivery (lipofection), a key first step in gene therapy.

Animals↗
PubMed1987

Experimental attempt to simulate receptor site environment. A 500-MHz 1H nuclear magnetic resonance study of enkephalin amides.

The amides of Leu5-enkephalin, Met5-enkephalin, and three analogues, D-Ala2,Leu5-enkephalin, (AcO)Tyr1,Met5-enkephalin, and (AcO)Tyr1,D-Ala2,Met5-enkephalin, have been studied by means of 1H NMR spectroscopy in two different solvent systems: Me2SO-d6 and CDCl3. In the latter solvent the peptides were dissolved as complexes with 18-crown-6-ether, a coronand that binds strongly to the NH3+ groups. The crown ether complexation and the apolar solvent were used to simulate the anionic subsite of the receptor and the hydrophobic environment of the receptor cavity, respectively. The very unusual amide proton chemical shifts and their temperature coefficients suggest the presence of folded conformations in CDCl3 for all peptides, consistent with several models of opioid receptors and with the crystal structure of Leu5-enkephalin. The differences among the proposed cyclic conformations of the five peptides may be correlated, in part, with their different biological activity. All peptides in Me2SO-d6 are characterized by complex mixtures of extended fully solvated conformations.

Enkephalin, Leucine↗
PubMed2002

Essential features of the catalytic core of peptidyl-alpha-hydroxyglycine alpha-amidating lyase.

Bioactive peptides frequently terminate with an essential alpha-amide that is generated from a COOH-terminal Gly in a two-step enzymatic process occurring within the lumen of the secretory pathway. The first enzyme, peptidylglycine alpha-hydroxylating monooxygenase, is a member of the copper- and ascorbate-dependent monooxygenase family. The second enzyme, peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL, EC 4.3.2.5), has no known homologues. Examination of the catalytic core of PAL (PALcc) using trypsin, BNPS skatole, and COOH-terminally truncated proteins failed to identify stable subdomains. Treatment of PALcc with divalent metal ion chelators inactivated the enzyme and increased its protease and thermal sensitivity, suggesting a structural role for bound metal. Purified PALcc contained 0.7 +/- 0.4 mol of zinc/mol of enzyme. Since the four Cys residues in PALcc form two disulfide bonds, potential Zn ligands include conserved Asp, Glu, and His residues. The secretion and activity of PALcc bearing mutations in each conserved Asp, Glu, and His residue were evaluated. Mutation of three conserved Asp residues and two conserved His residues yielded a protein that could not be secreted, suggesting that these residues play a structural role. Analysis of mutants that were efficiently secreted identified three His residues along with single Asp residue that may play a role in catalysis. These essential residues occur in a pattern unique to PAL.

Amidine-Lyases↗