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At least 361 records · Page 20Linked to original sources
PubMed1988

The novel CCK antagonist L364,718 abolished caerulein- but potentiates morphine-induced antinociception.

The novel CCK antagonist L364,718 was tested on caerulein- and morphine-induced antinociception in rat using the paw pressure test. Caerulein-induced antinociception (ED50 = 30 micrograms/kg) was significantly inhibited by L354,718 (200 micrograms/kg i.p.) which on its own did not affect paw pressure threshold. In contrast, morphine-induced antinociception was significantly potentiated by L364,718. Since L364,718 is highly selective for 'peripheral' receptors which are found in tissue such as pancreas and gallbladder and a few discrete areas of brain, this receptor is likely to be implicated in the antinociceptive effect of caerulein.

Analgesics↗
PubMed1989

Antagonism of central and peripheral anorectic effects of caerulein by L-364,718.

The reduction in food intake induced by i.p. injections of the cholecystokinin (CCK) analogue caerulein was antagonised by a low dose (0.25 mumol/kg s.c.) of the selective CCK antagonist L-364,718. To block the anorectic effect of centrally administered caerulein a dose of 25 mumol/kg of L-364,718 was required, demonstrating that central CCK receptors can be blocked effectively in the rat by choosing appropriate doses of L-364,718.

Animals↗
PubMed1990

Localization of peripheral cholecystokinin receptors in vivo using the cholecystokinin antagonist [3H](+/-)-MK-329.

Cholecystokinin (CCK) regulates various gastrointestinal functions through specific receptors. The mechanisms responsible for disorders of these functions could be elucidated by non-invasively localizing CCK receptors and quantifying their number in vivo. MK-329 is a highly selective and very high affinity antagonist at the peripheral CCK receptor. We investigated the in vivo binding of [3H](+/-)-MK-329 in mice to determine if binding to CCK receptors could be detected after systemic administration of the tracer. The uptake of [3H](+/-)-MK-329 increased in the pancreas from 5 min to 4 h after administration. The binding was saturable, stereospecific, and more than 80% specific. A total/non-specific binding ratio of 43 was reached at 8 h post-injection. The pancreas was the only organ where specific binding could be detected. Our results suggest that MK-329 labeled with a positron emitter such as C-11 could be used with positron emission tomography to image and quantify peripheral CCK receptors in man.

Animals↗
PubMed1990

Peptide receptor antagonists in the study of insulin and glucagon secretion in mice.

Peptide antagonists might be useful tools in elucidating a potential role for neuropeptides in islet hormone secretion. We therefore investigated the effects of three different peptide receptor antagonists on insulin and glucagon secretion in vivo in mice. The gastrin-releasing peptide (GRP) antagonist N-acetyl GRP-(20-26) amide (P less than 0.01) and the vasoactive intestinal polypeptide (VIP) antagonist [4Cl-D-Phe 6,Leu17] VIP (P less than 0.001) specifically inhibited insulin secretion induced by GRP and VIP, respectively. Furthermore, N-acetyl GRP-(20-26) amide specifically inhibited GRP-stimulated glucagon secretion (P less than 0.01) and the cholecystokinin (CCK) antagonist L-364,718 inhibited CCK-8-mediated insulin and glucagon secretion (P less than 0.001). However, neither of these three antagonists affected insulin or glucagon secretion stimulated by autonomic nerve activation (induced by 2-deoxy-glucose (2-DG)). We conclude that these peptide antagonists can be used in studies on the physiological involvement of GRP, VIP and CCK in islet hormone secretion. Furthermore, neither GRP or CCK seems involved in the insulin and glucagon response to 2-DG in the mouse.

Animals↗
PubMed1990

Characterization of neuronal cholecystokinin receptor by L-364,718 in Auerbach's plexus.

The release of [3H]acetylcholine [( 3H]ACh) from Auerbach's plexus and the contraction of longitudinal muscle strips in response to the administration of cholecystokinin (CCK) were measured and recorded simultaneously. The peripheral CCK receptor antagonist, 3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-1H- indole-2-carboxamide (L-364,718), antagonized the ACh releasing effect of CCK in a dose-dependent manner. The IC50 value and the dissociation constant (KD) were 41.0 +/- 2.0 pM and 0.06 +/- 0.01 nM, respectively. These results suggest that L-364,718 is a very potent antagonist of the neuronal CCK receptors.

Acetylcholine↗
PubMed1991

In vivo binding affinities of cholecystokinin agonists and antagonists determined using the selective CCKB agonist [3H]pBC 264.

The respective role of central vs. peripheral CCK-B receptors in the recently reported anxiolytic effects of CCK-B antagonists remains to be firmly established. We therefore investigated the in vivo binding properties of cerebral CCK receptors after i.c.v. injection into mice of [3H]pBC 264 ([3H]propionyl-Tyr(SO3H)-gNle-mGly- Trp-(NMe)Nle-Asp-Phe-NH2), a highly potent, peptidase-resistant and selective CCK-B agonist. The specific binding of [3H]pBC 264 was reversible and saturable. The dose producing 50% receptor occupancy was 25 pmol and the Bmax was 0.9 pmol/brain 15 min after injection. I.c.v. administered CCK8 (ID50 8500 pmol) was 200-fold less potent than pBC 264 (ID50 43 pmol) in inhibiting specific [3H]pBC 264 binding; CCK8NS, CCK5 and CCK4 being slightly less potent than CCK8. Aminopeptidases play a major role in degrading CCK8 since the protected analog pCCK8 or CCK8 in the presence of an aminopeptidase inhibitor exhibited higher affinities than CCK8. I.v. administration of pBC 264 (20 mg/kg) inhibited [3H]pBC 264 specific binding by about 72%, confirming its ability to enter the brain. In contrast, CCK4 was unable to modify [3H]pBC 264 binding. As expected, the CCK-A antagonist (L364,718) did not inhibit [3H]pBC 264 binding, while at the highest dose used (40 mg/kg i.p.) the CCK-B antagonist (L365,260) inhibited binding by 20%. Several hypotheses are discussed to account for the very low i.v. doses of CCK4 and L365,260 needed to produce anxiogenic and anxiolytic responses, respectively.

Amino Acid Sequence↗
PubMed1991

CCK-8-related C-terminal tetrapeptides: affinities for central CCKB and peripheral CCKA receptors.

We investigated the binding affinity of new tetrapeptides derived from the C-terminal sequence of CCK8 to central CCKB and peripheral CCKA receptors. Compound 1 (Boc-Trp-Met-Asp-Phe-NH2) showed high affinity for central CCKB receptors (Ki 4.2 x 10(-8) M, pancreas/cortex ratio = 283). Compounds 2 (Suc-Trp-Met-Asp-Phe-NH2) and 3 (Suc-Trp-Leu-Asp-Phe-NH2) also exhibited high affinity (Ki 2.7 x 10(-8) M and 5.6 x 10(-8) M, respectively) but their CCKB selectivity was nearly 50 times higher (Ki ratio greater than 14,000). Replacement of Met or Leu by other amino acids resulted in less effective tetrapeptides.

Amino Acid Sequence↗
PubMed1991

CCKA receptor antagonism inhibits mechanisms underlying CCK-8-stimulated insulin release in isolated rat islets.

The influence of the cholecystokinin (CCK)A receptor antagonist, L-364,718, on beta-cell activation was examined in isolated perifused prelabelled rat islets. Insulin secretion and 3H efflux from myo-[2-3H]inositol-prelabelled islets (reflecting phosphoinositide hydrolysis) stimulated by CCK-8 (100 nM) were both inhibited by L-364,718, partially at 1 nM and totally at 10 nM. 45Ca2+ efflux from prelabelled islets was markedly stimulated by CCK-8. This stimulation was inhibited equally by 1 and 10 nM L-364,718. CCK-8 stimulated the 86Rb+ efflux (reflecting K+ movements) from prelabelled islets, which probably reflects an indirect effect of CCK-8 due to opening of Ca(2+)-activated K+ channels. This 86Rb+ efflux was inhibited by L-364,718 at 10 nM but not affected by L-364,718 at 1 nM. It is concluded that insulin secretion, phosphoinositide hydrolysis, Ca2+ and K+ movements stimulated by CCK-8 in isolated islets are all events mediated by CCKA receptors. The L-364,718-induced inhibition of phosphoinositide hydrolysis was most closely correlated to the inhibition of insulin secretion. This suggests that induction of cellular events activated through stimulation of phosphoinositide hydrolysis is a major mechanism underlying CCK-8-stimulated insulin secretion.

Animals↗
PubMed1992

CCK-8-stimulated insulin secretion in vivo is mediated by CCKA receptors.

The effects of the cholecystokinin A (CCKA) receptor antagonist, L-364,718, and the CCKB receptor antagonist, L-365,260, on CCK-8-stimulated insulin secretion were studied in vivo in the mouse. It was found that CCK-8-stimulated insulin secretion was suppressed by L-364,718 at a low dose level (0.078 mumol/kg). In contrast, L-365,260 caused a partial inhibition of CCK-8-stimulated insulin release only at the high dose level (24 mumol/kg). It is concluded that the CCK-8-stimulated insulin release in vivo is mediated by CCK receptors of the CCKA subtype.

Animals↗
PubMed1992

Effects of bombesin, of a new bombesin agonist (BIM187) and a new antagonist (BIM189) on food intake in rats, in relation to cholecystokinin.

To study the mechanism by which bombesin induces satiety, we studied the effect of two new peptides, BIM187, a bombesin agonist, and BIM189, a bombesin antagonist, on food intake in rats fed 6 h a day. BIM187 at 4 micrograms/kg, significantly reduced food intake at 30 min, but did not change the total 6-h food intake. BIM189 (10 mg/kg), had no effect on food intake when administered alone, even at high doses (20 mg/kg). BIM189 selectively reduced bombesin-induced satiety but had no effect on satiety induced by BIM187. To examine the extent to which the satiety effect of bombesin or related peptides depends on the release of cholecystokinin (CCK), we studied the ability of CCK antagonists, BIM18216 and L364718, to reduce satiety induced by bombesin and BIM187. Neither BIM18216 nor L364718 alone had an effect on the 30-min food intake. They were not able to reverse the effect of bombesin on food intake. In our model, bombesin seems to act on satiety by a mechanism independent of CCK.

Animals↗
PubMed1993

Cholecystokinin-8 increases K(+)-evoked [3H] gamma-aminobutyric acid release in slices from various brain areas.

[3H] gamma-Aminobutyric acid (GABA) release was studied in rat brain slices in the absence or presence of cholecystokinin-8 (CCK-8). [3H]GABA release under the conditions used was Ca(2+)-dependent and insensitive to the presence of the glial uptake blocker beta-alanine. While the basal release of [3H]GABA was not affected by CCK-8, the K(+)-stimulated release of [3H]GABA was significantly enhanced by 300 nM of CCK-8 in the caudate putamen, the substantia nigra, the hippocampal formation and the parietofrontal cortex. In the cerebral cortex the CCK-8 enhancement of [3H]GABA release was concentration-dependent and abolished by the CCKB receptor antagonists PD135,158 (1.0 nM) and L-365,260 (100 nM). A significant counteraction of the CCK-8 action was also found with the CCKA receptor antagonist L-364,718 (100 nM) but only in concentrations at which both CCKA and CCKB receptors are blocked. No CCK-8 effects on [3H]GABA release were observed when tetrodotoxin was superfused 5 min before the K(+)-induced [3H]GABA release. It is suggested that the enhancing actions of CCK-8 on K(+)-stimulated [3H]GABA release is mainly related to an activation of CCKB receptors.

Animals↗
PubMed1993

Role of gastrin and cholecystokinin receptors in regulation of peptone-stimulated gastric acid secretion in conscious rats.

With the availability of selective gastrin/CCKB (L365,260) and CCKA (L364,718) receptor antagonists the present study was designed to investigate the role of gastrin and cholecystokinin (CCK) receptors in meal-stimulated gastric acid secretion. Gastric acid output was measured by continuous intragastric titration in conscious rats. Vehicle (dimethylsulfoxide/saline, 3:1), L365,260 (3 or 9 mg/kg), or L364,718 (1 mg/kg) was given by i.v. bolus injection. Basal acid output was strongly inhibited by both doses of L365,260 while L364,718 had no effect. Intragastric peptone (4%, w/v) increased acid secretion 40-65% of the response to a maximal dose (2.5 nmol/kg per h) of gastrin-17. L365,260 completely abolished gastrin-17 stimulated acid secretion and partially inhibited peptone-induced acid secretion. Blockade of CCKA receptors by L364,718 did not affect peptone-stimulated acid output. This study demonstrates that gastrin/CCKB receptors are important in regulating basal acid secretion in the conscious rat while CCKA receptors do not appear to influence basal or peptone-stimulated gastric acid secretion. Blockade of gastrin/CCKB receptors partially inhibits intragastric meal-stimulated acid secretion indicating that the gastrin/CCKB receptor has a physiological role as mediator of food-stimulated acid secretory response in conscious rats.

Animals↗
PubMed1993

Peripheral biological activity of SR 27897: a new potent non-peptide antagonist of CCKA receptors.

SR 27897 is a new non-peptide antagonist of CCKA receptors: 1-[[2-(4-(2-chlorophenyl)thiazol-2-yl)aminocarbonyl] indolyl] acetic acid. This compound is a potent ligand for CCKA binding sites (rat pancreatic membranes, Ki = 0.2 nM) and is highly selective (CCKB and gastrin/CCKA IC50 ratios of 800 and 5000 respectively). In vitro, it is a competitive antagonist of cholecystokinin (CCK)-stimulated amylase release in isolated rat pancreatic acini (pA2 = 7.50) and of CCK-induced guinea pig gall bladder contractions (pA2 = 9.57). In in vivo gastrointestinal models, SR 27897 confirmed the potency obtained in vitro: at 1 mg/kg (i.v.) it completely reversed the CCK-induced amylase secretion, at 3 micrograms/kg (p.o.) it antagonized by 50% the CCK-induced inhibition of gastric emptying of a charcoal meal in mice, and 72 micrograms/kg (p.o.) was the median effective dose for inhibiting CCK-induced gall bladder emptying in mice. SR 27897 was also very active (ED50 = 27 micrograms/kg p.o.) in the gall bladder emptying protocol with egg yolk as an inducer of endogenous CCK release. SR 27897 had a long-lasting action in all the experiments, with no differences between oral and intravenous routes of administration. SR 27897 was more or less effective than L-364,718, depending on the model and the species. Both compounds increased the gall bladder volume of fasting mice, but the effect of SR 27897 was 10 times lower than that of L-364,718. In summary, SR 27897 is a selective antagonist of CCKA receptors, is highly potent in animal models whatever the route of administration and has a long duration of action.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

CCKA receptors mediate slow depolarizations in cultured mammalian sympathetic neurons.

The effect of cholecystokinin octapeptide (CCK-8) was examined in guinea-pig celiac ganglion (CG) neurons in primary culture using standard intracellular recording techniques. Sulfated CCK-8 (CCK-8S; 1 microM) evoked slow depolarizing responses in 94% of CG neurons tested. In contrast, membrane potential was not affected by nonsulfated CCK-8 (CCK-8NS; 1 microM), CCK tetrapeptide (CCK-4; 1 microM), or gastrin (1 microM). The selective CCKA receptor antagonist L 364,718 potently inhibited CCK-8S-induced slow depolarizations (IC50 2.9 pM). In contrast, the selective CCKB receptor antagonist L 365,260 was a weak inhibitor of CCK-8S-induced slow depolarizations (IC50 1.3 microM). The depolarizing responses to CCK-8S were associated with an average increase in cell input resistance of 61%. Single electrode voltage clamp experiments indicated that CCK-8S-induced depolarizations were associated with a slow inward shift in holding current. Thus, the present findings indicate that guinea-pig cultured CG neurons are endowed with excitatory CCKA receptors the activation of which elicits a decrease in membrane conductance, thereby resulting in slow depolarizations.

Animals↗
PubMed1994

A cholecystokinin receptor antagonist, loxiglumide, stimulates biliary secretion in conscious rats.

The effects of the CCK receptor antagonists loxiglumide [D,L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxy-propylpentylam ino)-5-oxo- pentanoic acid, CR 1505] and MK-329 [3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo-diazepine-3-y l)-1H - indole-2-carboxamide, L-364,718], on bile flow were investigated in conscious rats. The bile duct of male Wistar rats was cannulated to directly collect pure bile, and the second cannula was inserted into the duodenum for reinfusion of bile. On the 4th through 7th postoperative days loxiglumide (25, 50 or 100 mg/kg body weight), MK-329 (1 mg/kg body weight) or the respective solvent (saline and 80% dimethyl sulfoxide) was injected subcutaneously. Loxiglumide caused dose-dependent increases in bile flow and bile acid output with a slight non-dose-dependent increase in bilirubin output. The integrated increments of bile flow during a 3-h period after saline and 100 mg/kg body weight loxiglumide were -14 +/- 71 and 982 +/- 61 microliters/100 g body weight, respectively, and those of bile acids were 2.5 +/- 1.4 and 23.1 +/- 4.1 mumol/100 g body weight, respectively. In contrast, MK-329 markedly decreased the bile flow (-439 +/- 76 vs. control; -32.8 +/- 76 microliters/100 g body weight/3 h, P < 0.001) and bile acids output (-16.3 +/- 6.8 vs. control; 3.4 +/- 3.8 mumol/100 g body weight/3 h, P < 0.001), while it significantly increased bilirubin output (86.4 +/- 15.6 vs. 43.5 +/- 1.1 mg/100 g body weight/3 h, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1996

His381 of the rat CCKB receptor is essential for CCKB versus CCKA receptor antagonist selectivity.

A great interest is devoted to antagonists of the cholecystokinin type B (CCKB) receptor such as L-365,260, which reduces panic attacks in humans and to antagonists of the cholecystokinin type A (CCKA) receptor, such as L-364,718 which might be efficient in mental diseases. The A/B specificity of these antagonists was proposed to be mainly dependent on the amino acid sequence of the seventh transmembrane domain (Mantamadiotis and Baldwin (1994) Biochem. Biophys. Res. Commun. 201,1382). In our study, one of these residues, His381 was replaced in the rat CCKB receptor by leucine (the corresponding residue in the CCKA receptor), phenylalanine or arginine using site-directed mutagenesis. Changing histidine for leucine or phenylalanine did not modify significantly the affinity of the CCKB receptor antagonists, L-365,260 and PD-134,308 although both compounds belong to different chemical classes, but strongly improved the affinity of the CCKA receptor antagonists tested. Interestingly, the A selectivity of these CCKA receptor antagonists was recovered by substituting His381 by arginine. Moreover, these results are discussed on the basis of a three dimentional model of the CCKB receptor. The mutated receptors possessed unchanged binding properties for agonists, suggesting that determinants confering specificity for agonists and antagonists are different.

Animals↗
PubMed1996

Synergistic interactions between human transfected adenosine A1 receptors and endogenous cholecystokinin receptors in CHO cells.

The effect of Gi coupled receptor activation (adenosine A1 and 5-HT1B receptors) on cholecystokinin receptor-stimulated inositol phosphate accumulation has been investigated in Chinese hamster ovary cells transfected with the human adenosine A1 receptor cDNA (CHO-A1). CHO cells constitutively express the 5-HT1B receptor [Berg, Clarke, Sailstad, Saltzman and Maayani (1994) Mol. Pharmacol. 46, 477-484]. Our previous studies using CHO-A1 cells have revealed that both the adenosine A1 and 5-HT1B receptor are negatively coupled to adenylyl cyclase activity and stimulate increases in [Ca2+]i, through a pertussis toxin-sensitive pathway. In the present study the selective adenosine A1 receptor agonist N6-cyclopentyladenosine stimulated a pertussis toxin-sensitive increase in total [3H]inositol phosphate accumulation. The sulphated C-terminal octapeptide of cholecystokinin (CCK-8) stimulated a robust and pertussis toxin-insensitive increase in [3H]inositol phosphate accumulation through the activation of CCKA receptors. Co-stimulation of CHO-A1 cells with N6-cyclopentyladenosine and CCK-8 produced a synergistic increase in [3H]inositol phosphate accumulation. The synergistic interaction between N6-cyclopentyladenosine and CCK-8 was abolished in pertussis toxin-treated cells. Synergy between N6-cyclopentyladenosine and CCK-8 still occurred in the absence of extracellular calcium. The 5-HT1B receptor agonist 5-carboxyamidotryptamine did not stimulate a measurable increase in [3H]inositol phosphate accumulation. Furthermore, 5-carboxyamidotryptamine had no significant effect on CCK-8 mediated [3H]inositol phosphate production. Activation of endogenous P2U receptors (Gq/Gll coupled) with ATP gamma S produced a significant increase in [3H]inositol phosphate accumulation. Co-stimulation of CHO-A1 cells with ATP gamma S and CCK-8 produced additive increases in [3H]inositol phosphate accumulation. These data indicate that CHO-A1 cells may prove a useful model system in which to investigate further the mechanisms underlying the intracellular 'cross-talk' between phospholipase C coupled receptors (Gq/Gll linked) and Gi/Go coupled receptors.

Adenosine↗