Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholecystokinin tetrapeptide (CCK4) induces symptoms similar to those of panic attack. The present study investigated the effects of CCK4 administration on catecholaminergic system. In this double blind, randomised, crossover experiment, 16 healthy subjects received injections of either 25 microg of CCK4 or placebo on two separate occasions. Platelet and plasma catecholamine concentrations were assessed before the administration and compared to post-injection values. The results clearly show that both plasma and platelet concentrations of catecholamines are significantly affected by CCK4. Plasma norepinephrine (NE) and epinephrine (EPI) raised significantly above baseline in the immediate post-CCK4 period, while in plasma dopamine (DA), the significant increases were delayed. In the platelets, significant post-CCK4 increases of NE and EPI concentrations were observed with a delay of several minutes. In summary, we have demonstrated that, in healthy subjects, CCK4 increases peripheral concentrations of catecholamines in both plasma and platelets, with the most consistent changes occurring in platelet NE and plasma EPI concentrations.
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PMID:CCK4-induced panic in healthy subjects II: neurochemical correlates. 1008 42

Stereotyped behavior can be induced by the dopamine agonist apomorphine or by the releasing agent amphetamine. Cholecystokinin influence on dopamine-mediated behaviors has been extensively studied but a real controversy remains. Our purpose was to further characterize the dopamine-cholecystokinin interaction in apomorphine- and amphetamine-induced stereotyped behavior using sulphated cholecystokinin octapeptide (CCK8) and cholecystokinin tetrapeptide (CCK4) treatments. The results showed that CCK8 decreases apomorphine-induced stereotyped behavior and CCK4 has no effect. CCK4 and CCK8 increased the amphetamine-induced stereotyped behavior; CCK4 was more effective. The results confirm the opposite modulation of apomorphine or amphetamine-induced stereotyped behavior by CCK. These data suggest that this modulation is mediated by both CCK receptors on apomorphine-induced and only by CCK(2) receptors on amphetamine-induced stereotyped behavior.
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PMID:Cholecystokinin modulation of apomorphine- or amphetamine-induced stereotypy in rats: opposite effects. 1145 23

Cholecystokinin peptides (CCK) have been shown to antagonize many opioid-mediated effects. The present study was undertaken to determine whether peripheral injections of cholecystokinin sulphated octapeptide (CCK8), cholecystokinin tetrapeptide (CCK4), the CCK(1) (lorglumide) and the CCK(2) (PD-135,158 and LY-225910) receptor antagonists can influence a classic morphine excitatory effect, i.e. the display of Straub tail reaction in mice (STR). A total of 570 female Balb/C mice were tested. Experiment 1 was undertaken to determine whether i.p. injections of CCK8 or CCK4 can influence STR. Each animal was treated with i.p. injections of saline or CCK8 (10 and 20 nmol/kg) or CCK4 (20 and 40 nmol/kg). After 30 min all animals received an i.p. injection of morphine hydrochloride (10.0 mg/kg). The highest doses of both CCK8 (35% STR) and CCK4 (40% STR) significantly reduced STR as compared to saline (85% STR) treated mice (Fisher test; P < 0.01). In experiment 2 each animal was treated with ip injections of saline or 1.0 mg/kg lorglumide or PD-135,158 fifteen minutes before an injection of morphine at doses ranging from 1.0 to 50.0 mg/kg. In experiment 3 animals were treated with injections of saline, 0.1 or 10.0 mg/kg lorglumide or LY-225910 before an injection of a fixed MC dose (2.0 mg/kg). Both lorglumide and PD-135,158 induced a significant shift to the left in the morphine dose-response curves as well as a significant decrease in ED50 of the STR. ED50 for lorglumide was significantly lower than ED50 for PD-135,158. Both doses of lorglumide and the highest dose of LY-225910 significantly increased the percent of animals displaying STR. Experiment 4 was undertaken to determine whether repeated peripheral injections of morphine or the morphine-potentiating agents CCK(1) (lorglumide) and the CCK(2) (LY-225910) receptor antagonists can induce morphine sensitization. Each animal was treated with 5 daily i.p. injections of saline (control group), 1.5 mg/Kg morphine hydrochloride (group morphine), and 1.0 mg/Kg lorglumide (group LOR) or LY-225910 (group LY). One, two, three and four weeks after the last treatment day, all animals were challenged with one i.p. injection of morphine (1.5 mg/Kg). The morphine, LOR groups and group LY showed a significant increase in percentage of animals displaying STR. These data demonstrate that the blockade of endogenous CCK actions leads to morphine sensitization probably through both CCK receptors. The present data are consistent with the antagonistic effects of CCK and opioids in the control of morphine-induced STR. In addition, these results suggest that both CCK receptors are involved in the modulatory effects of CCK on this morphine effect.
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PMID:Stimulation of either cholecystokinin receptor subtype reduces while antagonists potentiate or sensitize a morphine-induced excitatory response. 1145 24

Intestinal metabolism and poor permeability were known to be major barriers for oral absorption of large peptide drugs. Dimensionless wall permeability values of C-terminal octa- and tetra-peptides cholecystokinin analogs (CCK8 and CCK4) were estimated and found out to be greater than 1, suggesting no permeability-limited absorption for CCK analogs. Thus, a strategy employing enzyme inhibitors and a specific delivery site to improve the absorption was developed and tested with CCK8, followed by identification of metabolites of the analogs and their participating enzymes in rabbit brush-border membrane vesicles. Thiorphan and amastatin, a specific enzyme inhibitor for enkephalinase and aminopeptidase, respectively, in pH 4 buffer solution were coadministered with CCK8 to the ileum in fistulated rats. The absolute bioavailability (F) of CCK8 was 5.4% and increased to 19% in the presence of the enzyme inhibitors, while the F values following oral administration were close to zero. These results indicate that peptide oral delivery is possible.
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PMID:Intestinal metabolism and absorption of cholecystokinin analogs in rats. 1192 13

Our recent work on the intestinal metabolism and absorption of cholecystokinin analogs, sulfated C-terminal octapeptide (CCK8; Asp-Tyr(SO(3)H)-Met-Gly-Trp-Met-Asp-Phe(NH(2)) = DY(SO(3)H)MGWMDF(NH(2))) and tetrapeptide (CCK4; Trp-Met-Asp-Phe(NH(2)) = WMDF(NH(2))), was extended to investigate the degradative process of these analogs using rabbit jejunum brush-border membrane vesicles and to find a better enzyme-inhibitor system for intestinal absorption of peptide drugs. Various enzyme inhibitors and a lower pH buffer were applied to discover the major enzyme(s) involved in each process. Metabolic pathways showing degradative processes were proposed for both analogs. The major cleavage site occurs at the W(1)-M(2) for CCK4. At least three metabolic pathways occur independently for CCK8 and appear at peptides bonds between G(4)-W(5), M(6)-D(7), and D(7)-F(NH(2))(8). Many different enzymes of aminopeptidase, endopeptidase, angiotensin-converting enzyme, metalloenzyme, and others were involved in each process. Identification of more specific yet safe enzyme inhibitors and co-administration of various these inhibitors may lead to further enhancement in intestinal peptide absorption when administered orally.
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PMID:Possible degradative process of cholecystokinin analogs in rabbit jejunum brush-border membrane vesicles. 1240 43

Endocrine cells containing gastrin/cholecystokinin (CCK)-like immunoreactivity were localized to the islet tissue in the pancreas of the spiny dogfish. Most of these cells were located in the 'intestinal' lobe of the pancreas; only occasional cells were observed in the 'splenic' lobe. The gastrin/CCK-like immunoreactive cells were often co-localized with the 'classical' pancreas hormones (insulin, glucagon and somatostatin). Radioimmunoassay of water extracts with a C-terminally directed antiserum revealed high levels of immunoreactive material in the intestinal part (48.6 +/- 19.9 pmol/g) and lower levels (4.5 +/- 0.6 pmol/g) in the splenic part. Acetic acid extracts of the intestinal lobe contained low levels (6.8 +/- 3.3 pmol/g) of gastrin/CCK-like immunoreactivity, whereas corresponding extracts of the splenic part showed no immunoreactivity. When the extracts were subjected to DEAE ion-exchange chromatography the gastrin/CCK-like peptides eluted as a major peak. After Sephadex gel filtration, pooled immunoreactive material from the main DEAE chromatographic peak eluted at a position close to that of CCK4. Further characterization by ion-exchange and reversed-phase HPLC showed that, in general, the immunoreactive material behaved like the shorter forms of the gastrin/CCK family (CCK4/G5 and CCK8/Cae 3-10).
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PMID:Endocrine cells with gastrin/cholecystokinin-like immunoreactivity in the pancreas of the spiny dogfish, Squalus acanthias. 1250 16

At present there is an increasing literature demonstrating heterogeneity of the CCK-B receptor. Recent reports by our laboratory have demonstrated that the Fawn-Hooded rat demonstrates atypical neurochemical responses to CCK4, in vitro. Since the ability of CCK-B receptor ligands to modulate affective state is dependent on the putative receptor subtype activated, the aim of the present study was to examine the behavioural effects of the CCK-B receptor agonist, t-boc-CCK4, and the CCK-B receptor antagonist, Ci-988 in Fawn-Hooded and Wistar Kyoto rats. Interestingly, both t-boc-CCK4 and Ci-988 produced an anxiolytic profile in FH rats as determined by an increased time spent on the open arms of an elevated plus maze, while both drugs were devoid of any behavioural effect in WKY rats, lending further support to the theory that the FH rat strain has an atypical relative proportion of these putative subtypes apparently resulting in a predominantly CCK-B2 receptor effect.
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PMID:Atypical behavioural responses to CCK-B receptor ligands in Fawn-Hooded rats. 1457 8

The pharmacological profile of the new CCK1 receptor antagonist IQM-97,423, (4aS,5R)-2-benzyl-5-(tert-butylaminocarbonyl-tryptophyl)amino-1,3-dioxoperhydropyrido-[1,2-c]pyrimidine, was examined in in vitro and in vivo studies and compared with typical CCK1 antagonists such as devazepide and lorglumide. IQM-97,423 showed a high affinity at [3H]-pCCK8-labeled rat pancreatic CCK1 receptors, and was virtually devoid of affinity at brain CCK2 receptors. IQM-97,423 antagonized CCK8S-stimulated alpha-amylase release from rat pancreatic acini with a potency similar to devazepide and much higher than lorglumide. In the guinea pig isolated longitudinal muscle-myenteric plexus preparation, IQM-97,423 produced a full antagonism of the contractile response elicited by CCK8S and a weaker effect on the contraction elicited by CCK4, suggesting a selective antagonism at CCK1 receptors. The protective effect of IQM-97,423 and devazepide was tested in two models of acute pancreatitis in rats, induced by injection of cerulein or by combined bile and pancreatic duct obstruction. The new compound fully prevented the cerulein-induced increase in plasma pancreatic enzymes and in pancreas weight with a potency similar to devazepide. In common bile-pancreatic duct ligature-induced acute pancreatitis, IQM-97,423 partially prevented, like devazepide, the increase in plasma pancreatic enzyme activity and in pancreas weight. Consequently, the pyridopyrimidine derivative IQM-97,423 is a potent and highly selective CCK1 receptor antagonist with preventive effects in two experimental models of acute pancreatitis and a potential therapeutic interest.
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PMID:Pharmacological study of IQM-97,423, a potent and selective CCK1 receptor antagonist with protective effect in experimental acute pancreatitis. 1533 11

Cholecystokinin (CCK) is the most abundant neuropeptide in the mammalian brain, and has been implicated in the regulation of a diversity of emotions and motivations including negative affect and stress responses. In this experiment, we assayed levels of CCK (CCK4/5 and CCK8) from tissue homogenates in intruder animals 6 h after resident-intruder inter-male aggression. Intruder animals that demonstrated submissive behavior (freezing and 22-kHz ultrasonic vocalizations) had higher levels of CCK in the tegmentum and posterior cortex as compared to non-submissive (i.e., "Friendly") intruder animals. Ultrasonic vocalizations (22-kHz) were positively correlated with CCK levels in the tegmentum, posterior cortex and pituitary. These data suggest that CCK may play a role in the generation of negative affective states indexed by 22-kHz ultrasonic calls in certain regions of the brain.
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PMID:Regional brain cholecystokinin changes as a function of friendly and aggressive social interactions in rats. 1546 47

To test whether a turnlike arrangement is involved in the bioactive conformation of CCK4 analogues upon CCK1 receptor recognition, we describe the preparation of two series of CCK4 derivatives, in which the central dipeptide Met-Asp has been replaced by recognized beta-turn mimetics {(2S,5S,11bR)- and (2R,5R,11bS)-2-amino-5-carboxy-3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole (IBTM) and beta-turn dipeptide, 2-oxo-7-thio-1-azabicyclo[4.3.0]nonane (BTD)}. The incorporation of the indolizinoindole IBTM type II beta-turn mimetic is preferred over its type II' counterpart for efficient CCK1 receptor recognition, while BTD derivatives were completely inactive. The structure-conformation-activity relationship study in the IBTM series has shown some essential requirement of these CCK4 derivatives to favorably interact with CCK1 receptors: (a) the adoption of turnlike conformations, (b) the presence of an L-Phe residue and a C-terminal carboxamide moiety, and (c) the indole ring of the IBTM skeleton. Moreover, the existence of pi-pi interactions between the phenyl ring of d-Phe residues and the indole ring of IBTM framework is detrimental for binding affinity. A series of potent and selective CCK1 receptor antagonists, exemplified by compounds 8a and 8b, emerges among these IBTM-containing derivatives.
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PMID:Conformationally constrained CCK4 analogues incorporating IBTM and BTD beta-turn mimetics. 1630 7


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