sincalide and cholecystokinin-(26-33)

sincalide has been researched along with cholecystokinin-(26-33)* in 28 studies

Other Studies

28 other study(ies) available for sincalide and cholecystokinin-(26-33)

ArticleYear
[Blood serum cholecystokinin and clinical-functional variability of biliary pathology].
    Eksperimental'naia i klinicheskaia gastroenterologiia = Experimental & clinical gastroenterology, 2014, Issue:12

    Basal and stimulated serum CCK concentrations were not statistically significant differences (p > 0.05) with the control group in patients studied in the whole and in patients subgroups, formed by the diagnosis of biliary pathology and the character of gallbladder emptying. Increased stimulated CCK concentration was found in patients with symptomatic variants. Reduce of serum-cholecystokinin concentration growth (ACCK) after intake of Sorbitol was revealed in subgroup of patients with low-symptom variant. Reduced sensitivity of the gallbladder to CCK was observed in subgroups of patients with gallbladder hypokinetic dyskinesia and one with symptomatic variant of biliary pathology.. The sensitivity of the gallbladder neuromuscular apparatus to CCK is associated with clinical and functional variability of the biliary pathology.

    Topics: Adult; Biliary Tract Diseases; Case-Control Studies; Female; Gallbladder; Gallbladder Emptying; Humans; Male; Middle Aged; Sincalide; Ultrasonography

2014
Cholecystokinin exerts an effect via the endocannabinoid system to inhibit GABAergic transmission in midbrain periaqueductal gray.
    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2011, Volume: 36, Issue:9

    Cholecystokinin modulates pain and anxiety via its functions within brain regions such as the midbrain periaqueductal gray (PAG). The aim of this study was to examine the cellular actions of cholecystokinin on PAG neurons. Whole-cell patch clamp recordings were made from rat midbrain PAG slices in vitro to examine the postsynaptic effects of cholecystokinin and its effects on synaptic transmission. Sulfated cholecystokinin-(26-33) (CCK-S, 100-300 nM), but not non-sulfated cholecystokinin-(26-33) (CCK-NS, 100-300 nM) produced an inward current in a sub-population of opioid sensitive and insensitive PAG neurons, which did not reverse over a range of membrane potentials. The CCK-S-induced current was abolished by the CCK1 selective antagonist devazepide (100 nM), but not by the CCK2 selective antagonists CI988 (100 nM, 1 μM) and LY225910 (1 μM). CCK-S, but not CCK-NS produced a reduction in the amplitude of evoked GABA(A)-mediated inhibitory postsynaptic currents (IPSCs) and an increase in the evoked IPSC paired-pulse ratio. By contrast, CCK-S had little effect on the rate and amplitude of TTX-resistant miniature IPSCs under basal conditions and when external K(+) was elevated. The CCK-S-induced inhibition of evoked IPSCs was abolished by the cannabinoid CB1 receptor antagonist AM251 (3 μM), the mGluR5 antagonist MPEP (10 μM) and the 1, 2-diacylglycerol lipase (DAGLα) inhibitor tetrahydrolipstatin (10 μM). In addition, CCK-S produced an increase in the rate of spontaneous non-NMDA-mediated, TTX-dependent excitatory postsynaptic currents (EPSCs). These results suggest that cholecystokinin produces direct neuronal depolarisation via CCK1 receptors and inhibits GABAergic synaptic transmission via action potential-dependent release of glutamate and mGluR5-induced endocannabinoid signaling. Thus, cholecystokinin has cellular actions within the PAG that can both oppose and reinforce opioid and cannabinoid modulation of pain and anxiety within this brain structure.

    Topics: Animals; Cannabinoid Receptor Modulators; Cholagogues and Choleretics; Cholecystokinin; Endocannabinoids; Female; gamma-Aminobutyric Acid; Male; Neural Inhibition; Patch-Clamp Techniques; Periaqueductal Gray; Rats; Rats, Sprague-Dawley; Sincalide; Synaptic Transmission

2011
Extracellular signal-regulated kinase 1/2 signaling pathway in solitary nucleus mediates cholecystokinin-induced suppression of food intake in rats.
    The Journal of neuroscience : the official journal of the Society for Neuroscience, 2004, Nov-10, Volume: 24, Issue:45

    Increased food intake is a major factor in the development of obesity, and the control of meal size is a valid approach to reduce food intake in humans. Meal termination, or satiety, is thought to be organized within the caudal brainstem where direct signals from the food handling alimentary canal and long-term signals from the forebrain converge in the solitary nucleus. Cholecystokinin (CCK) released from the gut after ingestion of food has been strongly implicated in nucleus tractus solitarius (NTS)-mediated satiation, but the exact cellular and intracellular signaling events are not understood. Using Western blotting and immunohistochemistry with phosphospecific antibodies, we demonstrate here that peripheral administration of CCK in rats leads to rapid activation of the extracellular signal-regulated kinase (ERK) signaling cascade in NTS neurons and that blockade of ERK signaling with microinfusion of a selective mitogen-activated ERK kinase inhibitor into the fourth ventricle attenuates the capacity of CCK to suppress food intake. In addition, we show that CCK-induced activation of ERK results in phosphorylation of the voltage-dependent potassium channel Kv4.2 and the nuclear transcription factor CREB (cAMP response element-binding protein). The results demonstrate that ERK signaling is necessary for exogenous CCK to suppress food intake in deprived rats and suggest that this pathway may also be involved in natural satiation and the period of satiety between meals through coupling of ERK activation to both cytosolic and nuclear effector mechanisms that have the potential to confer acute and long-term changes in neuronal functioning.

    Topics: Animals; Brain Stem; Butadienes; Cyclic AMP Response Element-Binding Protein; Eating; Enzyme Activation; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Nitriles; Phosphorylation; Potassium Channels, Voltage-Gated; Protein Processing, Post-Translational; Rats; Satiation; Shal Potassium Channels; Signal Transduction; Sincalide; Solitary Nucleus

2004
A secretin i.v. infusion activates gene expression in the central amygdala of rats.
    Neuroscience, 2003, Volume: 118, Issue:4

    For the last 100 years secretin has been extensively studied for its hormonal effects on digestion. Recent observations that the deficits in social reciprocity skills seen in young (3-4-year-old) autistic children are improved after secretin infusions suggest an additional influence on neuronal activity. We show here that i.v. administration of secretin in rats induces Fos protein expression in the neurons of the central amygdala as well as the area postrema, bed nucleus of the stria terminalis, external lateral parabrachial nucleus and supraoptic nucleus. However, secretin infusion did not induce Fos expression in the solitary tract nucleus or paraventricular nucleus, regions normally activated by related peptides such as cholecystokinin. The peak blood levels of secretin that induce Fos protein expression in rat brain are similar to the peak blood levels observed during i.v. treatment with secretin in humans. The amygdala is known to be critical for developing reciprocal social interaction skills and abnormalities in this brain region have been demonstrated in autistic children.

    Topics: Amygdala; Animals; Area Postrema; Area Under Curve; Gene Expression Regulation; Humans; Immunohistochemistry; Infusions, Intravenous; Male; Neurons; Neuropeptides; Neurotransmitter Agents; Peptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Pons; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Secretin; Septal Nuclei; Sincalide; Supraoptic Nucleus; Time Factors; Vasoactive Intestinal Peptide

2003
[Effect of conjunctive instillation of cholecystokinin 26-33 on pancreatic endocrine function in type 1 diabetes mellitus].
    Fiziolohichnyi zhurnal (Kiev, Ukraine : 1994), 2003, Volume: 49, Issue:4

    To investigate the role of cholecystokinin (ChCK) in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) and to search the ways of its treatment with good prospects we conducted a comparative study of the effects of chronic conjunctive instillations (c.i.)) and intracerebroventricular administrations (i.c.v.) of cholecystokinin octapeptide (ChCK-8) to intact and streptozotocin-induced IDDM rats. The state of alpha- and beta-cells in pancreatic islets was studied by immunocytochemical method with a subsequent quantitative analysis on an automatic image analysis system. Our investigation has shown that in healthy rats both i.c.v. and c.i. administrations of ChCK-8 induced a significant increase in glycemia due to stimulation of alpha-cells and depression of beta-cells. However effects of ChCK-8 on the synthesis and secretion of insulin prevailed at i.c.v. administrations, while ChCK-8 administrated by c.i. was more potent in stimulating alpha-cells. Both ways of ChCK-8 administrations to a IDDM rats caused a positive effect on those animals by inhibiting a destruction of beta-cells, stimulating their function, and decreasing the content of alpha-cells in pancreatic islets which lead to a significant increase in insulin and a decrease in glucose in blood.

    Topics: Animals; Conjunctiva; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Injections, Intraventricular; Instillation, Drug; Insulin; Islets of Langerhans; Male; Rats; Rats, Wistar; Sincalide

2003
The effects of duodenal peptides on glucagon-like peptide-1 secretion from the ileum. A duodeno--ileal loop?
    Regulatory peptides, 2002, Dec-31, Volume: 110, Issue:1

    Secretion of the gut hormone glucagon-like peptide-1 (GLP-1) is stimulated by meal ingestion. The response is rapid, suggesting a stimulatory pathway elicited from the upper gastrointestinal area. In pigs, we have been unable to demonstrate a neural stimulatory pathway, but GLP-1 secretion is regulated by local somatostatin secretion. In search for an endocrine pathway, we studied the effect of a range of concentrations of cholecystokinin octapeptide (26-33) (CCK 8), gastric inhibitory peptide 1-42 (GIP), secretin, motilin, calcitonin gene-related peptide (CGRP), and the modified amino acid, 5-hydroxytryptamine (serotonin, 5-HT) on GLP-1 and somatostatin release from isolated perfused segments of porcine ileum.GLP-1 secretion was stimulated by 1 nM CCK 8 and 10 nM GIP, but suppressed by 1 nM motilin and 1 microM 5-HT. Secretin and CGRP had no effect. Somatostatin secretion was stimulated by CCK 8 at 1 and 10 nM, by GIP at 1 and 10 nM and by 10 nM CGRP. Secretin, 5-HT and motilin had no effect on somatostatin secretion. We conclude that CCK 8 and GIP 1-42 stimulated GLP-1 secretion, but only in concentrations greatly exceeding normal postprandial concentrations. Thus, we find it unlikely that endocrine agents from the duodenum regulate GLP-1 secretion in pigs.

    Topics: Animals; Calcitonin Gene-Related Peptide; Chemotherapy, Cancer, Regional Perfusion; Duodenum; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Ileum; Motilin; Peptide Fragments; Postprandial Period; Protein Precursors; Sincalide; Swine

2002
Sulfated cholecystokinin (26-33) induces mild taste aversion conditioning in rats when administered by three different routes.
    Peptides, 1998, Volume: 19, Issue:5

    We investigated the ability of sulfated cholecystokinin (26-33) (CCK-8) and cholecystokinin (30-33) (CCK-4) to induce taste aversion or avoidance conditioning (TAC) in a one-bottle testing paradigm after either intravenous (i.v.), intracerebroventricular (i.c.v.), or intraperitoneal (i.p.) administration. Significant TAC was induced by i.p. administration of CCK-8 at 0.1 but not at 0.025, 0.5, or 1.0 micromol/kg; the TAC was not robust and, in this case, not even dose related. I.p. administration of CCK-4 at 0.05, 0.1, 0.5, or 1.0 micromol/kg did not induce TAC, replicating other studies from our lab. Mild but significant TAC was also induced by i.v. administration of CCK-8 (at 0.025 and 1.0 but not 0.1 or 0.5 micromol/kg) but not by i.v. administration of CCK-4 (at 0.05, 0.1, 0.5, or 1.0 micromol/kg). Finally, mild but significant TAC was induced by i.c.v. (i.e., lateral ventricular) administration of CCK-8 (at 0.0015 but not at 0.015 micromol/brain) but not by i.c.v. administration of CCK-4 (at 0.005 or 0.010 micromol/brain). Because CCK-4 failed to induce TAC, CCK-8 apparently induced TAC via all three routes by an action at a CCK(a), not CCK(B), receptor mechanism. Because i.c.v. or i.v. administrations of CCK-8 were not more efficacious than i.p. administration, the taste avoidance induced by i.p. administration of CCK-8 was not so mild simply because it failed to reach a critical central locus adequately or because it failed to be delivered at a critical speed (i.e., via i.v. injections). We demonstrate that CCK-8 can induce mild TAC at either peripheral or central sites and suggest that these effects of CCK-8 may be independent and may be a sign of salience but not necessarily of toxicosis.

    Topics: Analysis of Variance; Animals; Avoidance Learning; Conditioning, Operant; Injections, Intraperitoneal; Injections, Intravenous; Injections, Intraventricular; Male; Rats; Sincalide; Sulfuric Acid Esters; Taste

1998
Diradylglycerol formation in cholecystokinin-stimulated rabbit pancreatic acini. Assessment of precursor phospholipids by means of molecular species analysis.
    European journal of biochemistry, 1996, Jan-15, Volume: 235, Issue:1-2

    The aim of the present study was to assess the origin of the 1,2-diradylglycerols produced during prolonged hormonal stimulation of rabbit pancreatic acini by comparison of their relative molecular species composition with that of the major acinar phospholipids. Both phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) consisted of 1,2-diacyl as well as 1-alk-1-2-acyl species. In contrast, phosphatidylinositol (PtdIns), phosphatidylserine and phosphatidic acid existed only in the 1,2-diacyl form. Acinar cells did not contain detectable amounts of 1-alkyl-2-acyl phospholipids. Similarly, the acinar 1,2-diradylglycerol fraction consisted of 1,2-diacylglycerols and 1-alk-1-enyl-2-acylglycerols. Mass 1,2-diradylglycerol measurements revealed that prolonged stimulation with cholecystokinin resulted in a marked and sustained increase in acinar 1,2-diradylglycerol content. Based on the relative amounts of the 1,2-diacyl species present in both the 1,2-diradylglycerol fraction and the individual phospholipids, it is calculated that under control conditions 60% of the 1,2-diacylglycerols originate from PtdCho and 40% from PtdIns, whereas under stimulatory conditions 53% is calculated to be derived from PtdCho, 46% from PtdIns and 1% from PtdEtn. Likewise, it is calculated that in control as well as stimulated acini 100% of the 1-alk-l-enyl-2-acylglycerols originate from plasmenylcholine. Further evidence in favour of the idea that at least a considerable part of the 1,2-diacylglycerols produced during prolonged hormonal stimulation originate from inositolphospholipids is provided by the observation that labeling of phosphatidylinositol 4,5-bisphosphate with inorganic phosphate reached isotopic equilibrium markedly faster under stimulatory conditions as compared to the control situation, which is in agreement with an elevated turnover rate. The data presented support the idea that PtdCho and inositolphospholipids are the major precursors in basal and stimulated 1,2-diradylglycerol production in rabbit pancreatic acini.

    Topics: Animals; Diglycerides; In Vitro Techniques; Kinetics; Molecular Structure; Pancreas; Phosphatidylcholines; Phosphatidylinositols; Phospholipids; Rabbits; Sincalide

1996
Cholecystokinin (CCK) and C-terminal fragments of CCK: effects of CCK-33, CCK-8 and CCK-4 in the cardiovascular system of diabetic rats.
    General pharmacology, 1996, Volume: 27, Issue:2

    The effect of cholecystokinin (CCK-33) and its fragments, CCK-8 and CCK-4, on arterial blood pressure and the function of isolated rat heart and catecholamine levels in plasma and from isolated heart tissue in diabetes mellitus were studied. The results indicated that, in diabetes, cardiovascular effects of CCK-33 and CCK-8 are diminished or abolished. Diabetes can change the response of the alpha- and beta-adrenergic system to CCK-33 and CCK-8 and the contents of catecholamines in heart tissue.

    Topics: Animals; Cholecystokinin; Diabetes Mellitus, Experimental; Epinephrine; Heart; Hemodynamics; Myocardium; Norepinephrine; Rats; Sincalide

1996
Long-lasting potentiation and depression by novel isoproterenol and cholecystokinin 8-S interactions in the dentate gyrus.
    Experimental brain research, 1994, Volume: 100, Issue:1

    In the in vitro hippocampal slice, novel interactions of a beta-adrenergic agonist (l-isoproterenol) and neuropeptide (cholecystokinin 8-S) differentially produce long-lasting modifications in the dentate gyrus. When co-applied, a low concentration of l-isoproterenol (50-75 nM) and cholecystokinin 8-S (1.0 microM) produce long-lasting depression of evoked action potentials (i.e., population spikes). In contrast, the same concentration of l-isoproterenol followed by a 30-min wash with artificial cerebrospinal fluid and application of cholecystokinin 8-S produces long-lasting potentiation of evoked action potentials. In neither condition are there corresponding modifications of excitatory post-synaptic potentials. These results indicate that l-isoproterenol and cholecystokinin 8-S temporally interact to differentially produce depression or potentiation of granule cell-activation In contrast to long-lasting modifications produced by continuous application of 1.0 microM l-iso-proterenol, in which both evoked action potentials and excitatory post-synaptic potentials are affected, the present novel paradigm may modify an extra-synaptic locus.

    Topics: Animals; Baclofen; Drug Synergism; Electric Stimulation; Evoked Potentials; Hippocampus; In Vitro Techniques; Isoproterenol; Long-Term Potentiation; Male; Neuronal Plasticity; Rats; Rats, Sprague-Dawley; Sincalide

1994
Determination of sulfated peptides by differential iodination.
    Biological chemistry Hoppe-Seyler, 1994, Volume: 375, Issue:3

    A sequential approach was developed to label tyrosine sulfate and peptides containing tyrosine sulfate selectively. Amino acids and peptides containing tyrosine and tyrosine sulfate were first iodinated using chloramine-T-method. Reaction products were determined by RP-HPLC. Mono- and biiodination of tyrosine and several model peptides was achieved within 120 s incubation time. Iodination of free tyrosine sulfate and sulfated cholecystokinin26-33 was less than 5%. After desulfation of the reaction products with 1 N HCl successful radioiodination of desulfated tyrosine was carried out whereas tyrosine did incorporate radioactive iodine only 10%. As shown by RP-HPLC specific labeling of tyrosine sulfate containing peptides with 125iodine was achieved.

    Topics: Amino Acid Sequence; Chloramines; Chromatography, High Pressure Liquid; Indicators and Reagents; Iodine; Iodine Radioisotopes; Kinetics; Molecular Sequence Data; Peptides; Sincalide; Sulfates; Sulfur Radioisotopes; Tosyl Compounds; Tyrosine

1994
Synthesis of human CCK26-33 and CCK-33 related analogues on 2,4-DMBHA and TMBHA.
    Journal of medicinal chemistry, 1993, Jun-11, Volume: 36, Issue:12

    New analogues of human cholecystokinin in which the Tyr(SO3H) has been replaced by Phe(p-CH2SO3Na), methionines by norleucines, and tryptophan by 2-naphthylalanine([Phe(p-CH2- SO3Na)27,Nle28,31,Nal30]-CCK26-33 and [Phe(p-CH2SO3Na)27,Nle7,28,31,Nal30]-CCK-33) were synthesized by Fmoc solid phase methodology on two different resins (2,4- dimethoxybenzhydrylamine- and 4-(benzyloxy)-2',4'-dimethoxybenzhydrylamine resins, 2,4-DMBHA and TMBHA resins, respectively). While the syntheses on the TMBHA appeared to be more sluggish than those carried out on the 2,4-DMBHA, both final crude products were of equivalent relative purity and after purification gave approximately the same final yields of analogues estimated to have a purity greater than 93% using RPHPLC and CZE. The peptides were further characterized by amino acid analysis and LSIMS. Phe(p-CH2SO3Na)27,Nle7,28,31,Nal30]-CCK-33 was submitted to 33 Edman cycles and shown to be the desired product with less than 3% preview. Both analogues were tested for their ability to stimulate amylase release from isolated rat pancreatic acini. In this assay, [Phe(p-CH2SO3Na)27,Nle28,31,Nal30]-CCK26-33 and Phe(p-CH2SO3Na)27,Nle7,28,31,Nal30]-CCK-33 were 10 and 30 times less potent than CCK-8, respectively.

    Topics: Amino Acid Sequence; Amylases; Animals; Benzhydryl Compounds; Cholecystokinin; Chromatography, High Pressure Liquid; Molecular Sequence Data; Pancreas; Rats; Resins, Plant; Sincalide

1993
Modification of "peptoid" CCK-B antagonists to probe requirements for CCK-B agonist activity.
    Bioorganic & medicinal chemistry, 1993, Volume: 1, Issue:1

    This paper describes the use of the non-peptidal N-(2-adamantyloxycarbonyl)-alpha-methyl tryptophan phenylethylamide template of the "peptoid" CCK B antagonist compounds 1 as a basis to probe the functional group requirements of the CCK B receptor in order to produce an agonist response. Comparison of the peptoid template with inter-group distances in a fully extended conformation of the endogenous CCK-B agonist CCK 30-33 led to the design of a series of compounds 2 containing additional Ph, COOH and CONH2, functions at distances from the Trp indole ring that are able to mimic those in the natural ligand. The effect of these modifications was then assessed by measurement of CCK B binding affinities and potential agonist efficacy was investigated by comparison with contraction of guinea-pig isolated stomach corpus muscle strip stimulated by the CCK-B agonist pentagastrin. All compounds showed sub-micromolar binding affinities with each series displaying discernible dependence on intermediate chain length. All compounds (except 2f) were shown to be good CCK B antagonists; no compounds showed significant agonist activity up to a concentration of 1 microM.

    Topics: Adamantane; Animals; Dipeptides; Gastric Mucosa; Guinea Pigs; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Pentagastrin; Peptoids; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sincalide; Stereoisomerism; Templates, Genetic; Tetragastrin

1993
Inhibitory effect of gastrin and cholecystokinin fragments on the secretion of triacylglycerol in rat hepatocytes.
    Hepatology (Baltimore, Md.), 1993, Volume: 18, Issue:5

    In this investigation we studied the influence of two gastrin fragments, pentagastrin and nonsulfated heptadecagastrin, and two cholecystokinin fragments, sulfated and desulfated cholecystokinin 26-33, on intracellular and secreted triacylglycerol in isolated hepatocyte cultures. Both gastrin fragments inhibited triacylglycerol release in a biphasic manner, exhibiting maximal effect at 0.1 nmol/L (nonsulfated heptadecagastrin) and 0.3 nmol/L (pentagastrin). At these concentrations triacylglycerol secretion was 42% (nonsulfated heptadecagastrin, p < 0.001) and 62% (pentagastrin, p < 0.001) lower than in cells untreated with gastrin. Sulfated cholecystokinin 26-33 caused a 35% decrease in triacylglycerol secretion at 0.1 nmol/L (p < 0.01), and desulfated cholecystokinin 26-33 caused a 53% decrease at 0.2 nmol/L (p < 0.001). In all experiments, the hormone-induced decrease in triacylglycerol secretion was accompanied by an increase in intracellular triacylglycerol content. The cholecystokinin-A receptor antagonist L-364, 718 did not affect the decrease in triacylglycerol secretion induced by 0.3 nmol/L pentagastrin, whereas the cholecystokinin-B receptor antagonist L-365, 260 inhibited the pentagastrin effect at concentrations above 50 nmol/L. These results suggest that gastrin, cholecystokinin or some other gastrinlike hormone (or all three) may play a previously unrecognized regulatory role with respect to hepatic very low density lipoprotein secretion.

    Topics: Animals; Benzodiazepinones; Cells, Cultured; Depression, Chemical; Devazepide; Gastrins; Liver; Male; Pentagastrin; Peptide Fragments; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Sincalide; Triglycerides

1993
Examination of the effects of cholecystokinin 26-33 and neuropeptide Y on responses of visual cortical neurons of the cat.
    Neuroscience, 1993, Volume: 52, Issue:2

    Extracellular recordings were made from 160 neurons in area 17 (n = 120) and area 18 (n = 40) of the visual cortex of anesthetized cats. Cells were classified according to their receptive field properties and their intracortical positions were evaluated histologically. Cholecystokinin 26-33, antagonists, (cholecystokinin 27-32, cholecystokinin 27-33 and proglumide), amino acids, neuropeptide Y and solvent vehicle (control), were administered to cells by microiontophoresis (cholecystokinin and neuropeptide Y) or by pressure (neuropeptide Y). The results of the tests with cholecystokinin 26-33 fell into four categories: enhancement (31%), suppression (24%), mixed, i.e. either biphasic responses or dose-related alterations in the direction of effect (20%), and no effect (25%). Enhancements of the visually elicited response were more prevalent in simple (43%) and unimodal/movement-sensitive (34%) cells than in complex (7%) cells. The converse was true for suppressions: 19% of simple cells, 24% of unimodal/movement-sensitive cells, and 31% of complex cells were suppressed. Thirty per cent of the unaffected cells were complex or unimodal/movement-sensitive; only 14% were simple. Cells in layers II-IV were more likely to have firing enhanced than suppressed by cholecystokinin 26-33. The converse was true for cells in layers V and VI, where 50% of responses were suppressed and only 22% were enhanced. Unaffected cells were found predominantly in layer III of areas 17, and the lower part of layer III and layer IV of area 18. Cholecystokinin 26-33 sometimes exerted delayed, response-suppressant effects; it also occasionally elevated responsiveness preferentially within the upper ranges (10-20 degrees/s) of velocity tuning curves. Cholecystokinin 26-33 altered the response-suppressant action of GABA in 11 of 19 visually sensitive cells. The peptide potentiated the visual responsiveness in half of the cells where cholecystokinin 26-33 diminished the GABA-induced suppressions (n = 8). The presumed antagonists either exerted no effect on firing or on cholecystokinin 26-33-induced effects, or had cholecystokinin 26-33-like actions themselves. There was a reversible partial antagonism of the effects of cholecystokinin 26-33 on only two of 11 cells tested. Neuropeptide Y injected by pressure or administered iontophoretically had variable and inconsistent effects on the visually evoked responses of 29 additional neurons from those described above. These effects were indisti

    Topics: Animals; Baclofen; Cats; Cholecystokinin; Evoked Potentials, Visual; gamma-Aminobutyric Acid; Iontophoresis; Neural Conduction; Neurons; Neuropeptide Y; Photic Stimulation; Proglumide; Sincalide; Tachyphylaxis; Visual Cortex

1993
Development of CCK-B antagonists.
    Neuropeptides, 1991, Volume: 19 Suppl

    Our approach to design small molecule non-peptide analogues of the neuropeptide cholecystokinin (CCK) has led to the discovery of the CCK-B antagonist 'dipeptoids'. A representative member of this series of compounds, PD134308 [R-(R*,R*)]-4-[[2-[[3-(1H-Indol-3-yl)-2-methyl-1-oxo-2- [[(tricyclo[3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl] amino]-1-phenylethyl]amino]-4-oxobutanoic acid has high affinity (Ki = 1.7 nM) and selectivity for the CCK-B receptor (CCK-A/B ratio is 2500:1), is well absorbed and shows robust anxiolytic properties in several anxiogenic models in a dose related manner by both s.c. and oral routes of administration over the dose range 0.1-30 mg/Kg. The rational design of these dipeptoids from CCK 26-33 has involved the identification of the non-contiguous dipeptide fragment of CCK, Boc-Trp-Phe-NH2 with low micromolar affinity in binding assays. This dipeptide has been systematically chemically modified at the N- and C-terminal to increase CCK-B binding affinity 10,000-fold. These modifications include replacement of the L-tryptophan moiety by the non-genetically coded D-alpha-methyltryptophan residue. The modifications also enhance the stability of the molecule towards enzymatic and acid degradation and increase overall lipophilicity compared with the peptide in order to facilitate penetration of the blood-brain barrier.

    Topics: Amino Acid Sequence; Animals; Binding Sites; Blood-Brain Barrier; Cerebral Cortex; Cholecystokinin; Drug Design; Indoles; Meglumine; Mice; Molecular Sequence Data; Peptide Fragments; Receptors, Cholecystokinin; Sincalide; Structure-Activity Relationship

1991
Establishment of a new human pancreatic adenocarcinoma cell line, MDAPanc-3.
    Pancreas, 1990, Volume: 5, Issue:1

    A new cell line was established from a liver metastasis of a human pancreatic adenocarcinoma. The cell line, MDAPanc-3, which arose from a moderately differentiated adenocarcinoma, produces carbonic anhydrase II mRNA, but no detectable levels of insulin or alpha amylase mRNA. The stem line chromosome number was determined to be 43, with six marker chromosomes. Growth of MDAPanc-3 is stimulated by cholecystokinin (CCK) fragment 26-33. The cell line will be useful in further studies on the mechanism(s) by which CCK stimulates growth of certain human pancreatic adenocarcinomas and normal human pancreatic exocrine tissue.

    Topics: Adenocarcinoma; alpha-Amylases; Blotting, Northern; Cell Division; Humans; Insulin; Karyotyping; Keratins; Male; Middle Aged; Molecular Weight; Pancreatic Neoplasms; Protein Biosynthesis; RNA, Neoplasm; Sincalide; Tumor Cells, Cultured

1990
Cholecystokinin tetrapeptide induces panic-like attacks in healthy volunteers. Preliminary findings.
    Archives of general psychiatry, 1989, Volume: 46, Issue:6

    A total of 31 intravenous injections of the tetrapeptide cholecystokinin (30-33) were carried out in ten healthy subjects. In seven subjects, cholecystokinin-4 provoked a short-lasting (one to four minutes) panic-like attack (an intense unexplainable fear) at doses between 20 and 100 micrograms. In the other three subjects, doses of 80 to 100 micrograms induced severe anxiety, but no panic-like attack. All subjects experienced severe gastrointestinal symptoms. Pretreatment with lorazepam, but not with meprobamate or naloxone, prevented the psychic effects of cholecystokinin-4 in subjects who had experienced a panic-like attack with the same dose of this peptide. Following the peptide injection, levels of plasma free catecholamines, lactate, and glucose were unchanged, whereas levels of plasma cortisol and prolactin were increased. The intravenous injection of the sulfated cholecystokinin octapeptide (26-33) in two subjects (doses of 35 and 40 micrograms, respectively) produced severe gastrointestinal symptoms, but failed to induce any anxiety or panic-like attacks. These preliminary findings suggest that cholecystokinin-4 may have a panic-inducing effect. It remains to be established if this peptide exerts this effect via a direct activation of central cholecystokinin receptors.

    Topics: Adult; Anxiety Disorders; Blood Pressure; Brain; Cholecystokinin; Dopamine; Epinephrine; Fear; Female; Heart Rate; Humans; Hydrocortisone; Injections, Intravenous; Male; Norepinephrine; Panic; Peptide Fragments; Prolactin; Receptors, Cholecystokinin; Sincalide

1989
Synthesis and biological activity of CCK26-33-related analogues modified in position 31.
    Journal of medicinal chemistry, 1988, Volume: 31, Issue:5

    The role of the amino acid in position 31 of cholecystokinin CCK26-33 in the recognition of central and peripheral receptors was investigated by replacement of methionine-31 by amino acids with side chains of various chemical nature. Thus, phenylalanine, alanine, glutamic acid, and ornithine and its analogue with the epsilon-amino group protected by a benzyloxycarbonyl group were introduced as X residues in Boc(Nle28,X31)-CCK27-33 since the related analogue Boc(Nle28,Nle31)-CCK27-33 was shown to be equipotent to CCK26-33. The binding properties to both mouse brain membranes and guinea pig pancreatic acini and the peripheral activities (amylase secretion and contractile potency on guinea pig ileum) were determined. Whereas the introduction of phenylalanine, alanine, or ornithine residues in position 31 led to compounds that still displayed peripheral agonist properties, the presence of a negative charge in the side chain of the amino acid in position 31 prevented the binding of the peptide to both pancreatic and brain binding sites. Introduction of Phe31 and Ala31 residues increased the specificity of the peptides for the central receptors. Interestingly, when the amine function in the side chain of the ornithine-31 was protected by a benzyloxycarbonyl group, an unusual high affinity for pancreatic binding sites was observed and the related analogue proved to be a new peripheral CCK antagonist.

    Topics: Amino Acids; Amylases; Animals; Binding Sites; Binding, Competitive; Brain; Chemical Phenomena; Chemistry; Guinea Pigs; In Vitro Techniques; Mice; Muscle Contraction; Muscle, Smooth; Pancreas; Sincalide; Structure-Activity Relationship

1988
Optical absorbance changes induced by CCK-8 under limited O2 supply in isolated perfused rat pancreas.
    The American journal of physiology, 1988, Volume: 254, Issue:6 Pt 1

    Optical absorbance spectra were recorded simultaneously and continuously in the isolated rat pancreas arterially perfused at various flow rates. This was done to explain how optical absorbance changes corresponding to parallel reduction of cytochromes aa3, b, and cc1 were observed in perfused pancreas stimulated with high concentration of an exocrine secretagogue such as cholecystokinin-(26-33) (CCK-8). With perfusion flow rate between 1.5 and 3.0 ml/min, there were no optical absorbance changes corresponding to cytochrome reduction, but these optical absorbance changes occurred when the perfusion flow rate was decreased to 1.0 ml/min. These optical absorbance changes were not observed during exocrine secretion stimulated by CCK-8 (30 pM, 100 pM, and 1 nM) at the perfusion flow rate of 3.0 ml/min. Transient but slight changes in optical absorbances, which correspond to reduction of cytochromes, were observed in the glands perfused at the flow rate of 2.0 ml/min when secretion was stimulated by 1 nM CCK-8. When the perfusion flow rate was decreased to 1.0-1.5 ml/min, these optical absorbance changes corresponding to reduction of cytochromes occurred in glands stimulated by CCK-8 (30 pM, 100 pM, and 1 nM). Optical absorbance changes corresponding to reduction of mitochondrial cytochromes during secretion stimulated with CCK-8 may indicate local hypoxia in the perfused organ.

    Topics: Animals; Cytochromes; Dose-Response Relationship, Drug; Male; Mitochondria; Oxidation-Reduction; Oxygen; Pancreas; Pancreatic Juice; Perfusion; Rats; Rats, Inbred Strains; Sincalide; Spectrophotometry

1988
Investigation of peripheral cholecystokinin receptor heterogeneity by cyclic and related linear analogues of CCK26-33: synthesis and biological properties.
    Journal of medicinal chemistry, 1987, Volume: 30, Issue:6

    A possible heterogeneity of peripheral receptors for CCK26-33 [Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] (CCK8) was investigated by replacement of the flexible Gly29 residue, reported to be crucially involved in the CCK8 folding, by a D-Lys residue in Boc[Nle28,31]CCK27-33, a derivative as active as CCK8. The linear peptide Boc-Asp-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 was cyclized through amide bond formation between the side chains of Asp26 and D-Lys29 to give the peptide Boc-Asp-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2. Analogues 1 and 2 were shown to stimulate secretion of amylase from rat pancreas with a potency that was respectively 40 and 80 times lower than that of CCK8. In contrast, both peptides acted as weak antagonists (EC50 approximately 10(-5) M) of the CCK8-induced contractions of guinea pig ileum. Peptides 3 and 4 obtained by removal of the phenylalanine from 1 and 2 were inactive in all bioassays despite amidification of their C-terminal Asp32 residue, a modification known to induce antagonist properties in CCK7. Cyclization between residues 28 and 31 in Boc[Asp28,Lys31]CCK27-33 gave compound Boc-Tyr(SO3H)-Asp-Gly-Trp-Lys-Asp-Phe-NH2, which was inactive in all bioassays. The pharmacological properties of these first described cyclic analogues of CCK8 were in agreement with their binding affinity to brain and pancreas receptors, suggesting the existence of a heterogeneity of peripheral receptors and emphasizing the usefulness of cyclic peptides in structure-activity studies.

    Topics: Amylases; Animals; Guinea Pigs; In Vitro Techniques; Mice; Muscle Contraction; Rats; Receptors, Cholecystokinin; Sincalide; Structure-Activity Relationship

1987
Role of sulfate ester in influencing biologic activity of cholecystokinin-related peptides.
    The American journal of physiology, 1987, Volume: 252, Issue:2 Pt 1

    In dispersed acini from guinea pig, mouse, or rat pancreas cholecystokinin-(27-33) is a full agonist, and removing the sulfate ester from the tyrosine residue in position 27 caused a 100- to 300-fold decrease in potency with no change in efficacy. In dispersed acini from mouse or rat pancreas, cholecystokinin-(27-32)-NH2 is a partial agonist, and removing the sulfate ester from the tyrosine in position 27 abolished the efficacy. The desulfated peptide was able, however, to interact with CCK receptors with a potency that was threefold less than that of cholecystokinin-(27-32)-NH2 and therefore functioned as a cholecystokinin receptor antagonist. In dispersed acini from guinea pig pancreas cholecystokinin-(27-32)-NH2 is a cholecystokinin receptor antagonist. Removing the sulfate ester from the tyrosine residue in position 27 of cholecystokinin(27-32)-NH2 caused a fourfold decrease in potency but did not abolish the ability of the peptide to interact with cholecystokinin receptors; therefore, desulfated cholecystokinin-(27-32)-NH2 functioned as a cholecystokinin receptor antagonist.

    Topics: Amylases; Animals; Carboxylic Acids; Cholecystokinin; Esters; Guinea Pigs; Male; Mice; Pancreas; Peptide Fragments; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Sincalide; Structure-Activity Relationship; Sulfates

1987
Structure-activity studies of C- and N-terminal fragments of cholecystokinin 26-33 in guinea pig isolated tissues.
    Neuropeptides, 1987, Volume: 10, Issue:1

    In vitro structure-activity studies with cholecystokinin (CCK)/gastrin-related peptides, including C- and N-terminal fragments of CCK 26-33, were undertaken in guinea pig gallbladder and ileum. The general order of potency in both smooth muscle preparations is CCK 26-33 greater than CCK 1-33 greater than 27-33 much much greater than nonsulfated (NS) CCK 26-33 greater than pentagastrin greater than CCK 30-33. None of the CCK fragments exhibit antagonistic properties such as in guinea pig, rat and mouse pancreatic acinar cells and hog duodenum. These observations suggest the existence of CCK receptor sub-types in peripheral tissues.

    Topics: Animals; Dose-Response Relationship, Drug; Gallbladder; Guinea Pigs; Ileum; In Vitro Techniques; Male; Muscle, Smooth; Receptors, Cholecystokinin; Sincalide; Structure-Activity Relationship

1987
Antagonists of central and peripheral behavioral actions of cholecystokinin octapeptide.
    The Journal of pharmacology and experimental therapeutics, 1986, Volume: 236, Issue:2

    Pharmacological studies on the behavioral functions of sulfated cholecystokinin (CCK) in the gut and in the brain require potent, specific antagonists to CCK. Compounds identified as competitive antagonists at the peripheral receptors for CCK were tested for their ability to block the behavioral effects of CCK administered centrally and peripherally. Behavioral effects of CCK (8.8 X 10-10 mmol) administered centrally into the nucleus accumbens, i.e., potentiation of dopamine-induced hyperlocomotion in rats, were effectively blocked by pretreatment with proglumide (6 X 10(-5) mmol of nucleus accumbens), by benzotript (3 X 10(-5) mmol of nucleus accumbens) and by rabbit antiserum raised against CCK (0.2 microliter/nucleus accumbens), but not by CCK26-33 (1.7 X 10(-7) mmol) or unsulfated CCK26-33 (1.9 X 10(-6) mmol). The behavioral effects of peripherally administered CCK, i.e. reduced food consumption and reduced exploratory behaviors in mice, were blocked effectively by pretreatment with proglumide (0.3-0.9 mmol/kg), and by benzotript (0.03 mmol/kg), but not by CCK30-33 (0.003 mmol/kg). None of the compounds administered peripherally significantly affected food consumption or exploratory behaviors when given alone. Furthermore, none of the compounds significantly affected locomotion when administered alone into the nucleus accumbens, or significantly affected dopamine-induced hyperlocomotion when given into the nucleus accumbens before dopamine. Benzotript, proglumide and a CCK antibody appear to act as specific antagonists of the behavioral effects of CCK at both the peripheral gastrointestinal site and at the central nucleus accumbens site. Neither unsulfated CCK26-33 or CCK30-33 were effective as antagonists of peripheral or central behavioral effects of CCK. However, whereas benzotript and proglumide may be useful as pharmacologically specific antagonists, the high doses required suggest that more potent CCK antagonists are required for investigating the behavioral functions of endogenous CCK.

    Topics: Animals; Behavior, Animal; Benzamides; Brain; Dopamine; Dose-Response Relationship, Drug; Eating; Exploratory Behavior; Immune Sera; Male; Mice; Motor Activity; Nucleus Accumbens; Proglumide; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, Cholecystokinin; Sincalide

1986
Conformational analysis of cholecystokinin CCK26-33 and related fragments by 1H NMR spectroscopy, fluorescence-transfer measurements, and calculations.
    Biochemistry, 1986, Jul-01, Volume: 25, Issue:13

    The conformational behavior of CCK7, Tyr-Met-Gly-Trp-Met-Asp-Phe-NH2, and CCK8, Asp-Tyr-Met-Gly-Trp-Met-Asp-Phe-NH2, in their sulfated and unsulfated forms, was studied both by 1H NMR spectroscopy in dimethyl-d6 sulfoxide and water and by fluorescence-transfer measurements at pH 7. In neutral conditions, both experimental methods show that these peptides exist preferentially in folded forms with beta and gamma turns around the sequence Gly-Trp-Met-Asp and Met-Asp-Phe-NH2, respectively. The presence of stable folded conformations is supported by through-space effects during the titration of the ionizable groups and by the weak temperature dependency of some amide protons not only in dimethyl sulfoxide but also in water. The folding of the C-terminal part, already shown in CCK5, seems to be a common conformational characteristic in CCK peptides. The N-terminal part of CCK8 presents an equilibrium between beta and gamma turns, whereas this part of the peptide is more flexible in CCK7. The low quantum yield of Tyr and the large mean distance (R = 15 A) between Tyr and Trp, determined by fluorescence-transfer measurements, support the occurrence of folded conformations pushing the aromatic rings far from each other. Interestingly, the introduction of the sulfate group enhances the folding tendency even in aqueous medium. The larger amide temperature dependency and the decrease in the R distance at acidic pH suggest that an intramolecular ionic interaction involving the N-terminal amino group and the beta-carboxyl groups of Asp32 stabilize the folded forms. Metropolis calculations performed on CCK8 support the existence of stable folded conformations closely related to those deduced from experimental data.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Amino Acid Sequence; Cholecystokinin; Energy Transfer; Magnetic Resonance Spectroscopy; Peptide Fragments; Protein Conformation; Sincalide; Spectrometry, Fluorescence; Structure-Activity Relationship

1986
Hepatic processing of cholecystokinin peptides. I. Structural specificity and mechanism of hepatic extraction.
    The American journal of physiology, 1986, Volume: 250, Issue:3 Pt 1

    Since the liver is a target tissue of many biologically important molecules, we have studied the hepatic uptake of cholecystokinin (CCK) with the isolated, perfused rat liver and a series of radioiodinated and unlabeled CCK peptides. Of the naturally occurring forms of CCK, cholecystokinin octapeptide (CCK-8) was extensively extracted (26 +/- 0.7% of Bolton-Hunter-labeled CCK-8, 59% of unlabeled CCK-8) in a single pass through the liver, while CCK-33 was minimally extracted (3.1 +/- 1.2% of Bolton-Hunter-labeled CCK-33). Studies of structural specificity showed that the sulfate ester on the tyrosine residue of CCK-8 decreased its hepatic extraction, that the carboxyl-terminal tetrapeptide region of CCK-8 was more important for this uptake process than was the amino-terminal tetrapeptide region, and that oxidation reduced uptake of CCK. First-pass hepatic extraction of unlabeled CCK-8 was shown to be a high-capacity process; however, uptake of radioiodinated CCK-8 was partially saturable with unlabeled CCK-4. Specific lectins (wheat-germ agglutinin, concanavalin A) and a bile acid (taurocholate) inhibited hepatic extraction of CCK-8 in a concentration-dependent manner. These data are consistent with a highly specific cellular extraction process for CCK in the liver.

    Topics: Animals; Cholecystokinin; Iodine Radioisotopes; Liver; Male; Peptide Fragments; Perfusion; Rats; Rats, Inbred Strains; Sincalide; Structure-Activity Relationship

1986
N-terminal fragments of CCK-(26-33) as cholecystokinin receptor antagonists in guinea pig pancreatic acini.
    The American journal of physiology, 1985, Volume: 248, Issue:1 Pt 1

    In the present study we synthesized different N-terminal fragments and analogues of the C-terminal octapeptide of cholecystokinin [CCK-(26-33)] and examined their actions on dispersed acini prepared from guinea pig pancreas. None of the N-terminal fragments or analogues altered basal amylase release. Analogues of CCK-(26-32), CCK-(26-31), and CCK-(26-30) inhibited CCK-(26-33)-stimulated amylase, and there was a close correlation between the ability of an analogue to inhibit stimulated amylase and the analogue's ability to inhibit binding of 125I-cholecystokinin. N-acetyl-CCK-(26-29)-amide at concentrations as high as 100 microM did not inhibit CCK-(26-33)-stimulated amylase release or binding of 125I-CCK. For those analogues that antagonized CCK-(26-33)-stimulated amylase release the antagonism was of the competitive type and was specific for those secretagogues that interact with the cholecystokinin receptor. Removing the C-terminal amide from N-acetyl-CCK-(26-31)-amide caused a 10-fold decrease in the inhibitory potency, whereas removing the C-terminal amide from N-acetyl-CCK-(26-30)-amide did not alter the inhibitory potency of the peptide. Removing the sulfate ester from the tyrosine residue in position 27 of N-acetyl-CCK-(26-31) did not alter the inhibitory potency of the peptide, whereas removing the sulfate ester from the tyrosine residue in position 27 of N-acetyl-(26-30) caused a three- to fivefold decrease in the inhibitory potency of the peptide.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Amylases; Animals; Cholecystokinin; Guinea Pigs; Kinetics; Male; Pancreas; Receptors, Cell Surface; Receptors, Cholecystokinin; Sincalide; Structure-Activity Relationship

1985
CCK26-33 degrading activity in brain and nonneural tissue: a metalloendopeptidase.
    Journal of neurochemistry, 1985, Volume: 45, Issue:3

    Cholecystokinin octapeptide (CCK26-33) is metabolized by neural membranes with an initial cleavage to CCK29-33 and subsequent breakdown to CCK31-33 and CCK32-33; this pattern of proteolysis occurs on incubation with either P2 or purified lysed synaptosomal membranes. To determine whether the pattern of CCK26-33 proteolysis is unique to the brain and whether regional brain differences in its pathway or rate exist, we analyzed the proteolysis of CCK by synaptic membranes of various brain areas and cellular membranes of peripheral tissue. The pattern of degradation in brain did not differ among the regions studied. The overall proteolysis rate, as measured by the formation of tryptophan, was higher in the striatum than in the cortex, although CCK29-33 was formed at the same rate in both areas. In nonneural tissue, the rate of degradation was highest in liver membranes and lowest in pancreatic acinar cell preparations. Thus, it appears that degradative peptidases are not necessarily colocalized with CCK receptors. The pattern of product formation is the same in peripheral compared with CNS membranes; thus, the degradative pathway does not appear to be unique to brain tissue. The enzyme present in synaptic membranes that is responsible for CCK29-33 formation requires a metal ion and sulfydryl groups for the catalysis and thus is a metalloendopeptidase. Furthermore, its activity is inhibited by Ac-Gly-Phe-Nle-al, a peptide aldehyde whose sequence bears some homology to the amino acid sequence in the region of CCK26-33 that is cleaved by this enzyme.

    Topics: Animals; Brain; Cerebellum; Corpus Striatum; Endopeptidases; Liver; Male; Metalloendopeptidases; Pancreas; Protease Inhibitors; Rats; Rats, Inbred Strains; Sincalide; Synaptic Membranes

1985