Proglumide and benzotript: members of a different class of cholecystokinin receptor antagonists.

Hahne, William F.; Jensen, Robert T.; Lemp, George F.; Gardner, Jerry D.

doi:10.1073/pnas.78.10.6304

Cited by 176 publications

(72 citation statements)

References 19 publications

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“…First, removal of CCK from incubation medium did not abolish its inhibitory action, indicating that continued occupancy of the CCK receptor by tightly bound CCK leads to residual inhibition of EGF internalization (22). Second, proglumide, a competitive antagonist of CCK (23), blocked the inhibitory action of CCK. Third, caerulein, desulfated-CCK8, and pentagastrin inhibited 125I-EGF binding in parallel to their known potencies with respect to stimulation of amylase release and inhibition of 1251-CCK binding in pancreatic acini (25 465 blasts, and 3T3 cells) at 370C but not at 40C, a temperature that is known to inhibit EGF internalization (11).…”

Section: Discussionmentioning

confidence: 99%

Cytosolic calcium regulates epidermal growth factor endocytosis in rat pancreas and cultured fibroblasts.

Korc¹,

Matrisian²,

Magun³

1984

Proc. Natl. Acad. Sci. U.S.A.

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Cholecystokinin octapeptide (CCK8), the COOH-terminal moiety of cholecystokinin (CCK), exerted a rapid inhibitory effect on total cell-associated 125I-labeled epidermal growth factor As in the case of a number of other polypeptide hormones, high concentrations of EGF decrease the number of EGF receptors on the cell surface through a process called "downregulation." EGF binding and internalization are also modulated by a variety of nonphysiological agents. Thus, binding of EGF to its receptor is altered by phorbol esters (4), cyclamates (5), quinone derivatives (6), and teleocidine B (7), whereas EGF internalization is inhibited by dansylcadaverine, amantadine, and rimantidine (8). The physiological relevance of these observations is not easily apparent, inasmuch as these compounds are not normally found in vivo.Recently, platelet-derived growth factor (9), fibroblast-derived growth factor (10), the neurohypophyseal hormone vasopressin (11), and cholecystokinin (CCK) (12) have also been shown to inhibit EGF binding. These observations suggest that compounds other than EGF may modulate EGF binding activity in vivo. We now report that the inhibitory effect of CCK on EGF binding in isolated rat pancreatic acini may be due to Ca2+-mediated inhibition of EGF internalization. In support of this hypothesis, we demonstrate that the Ca2+ ionophore A23187 inhibits the internalization of 1251I-labeled EGF (1251I-EGF) in A-431 human carcinoma cells and other cultured fibroblasts. Inasmuch as a variety of hormones and neurotransmitters are known to act through Ca2 , it is possible that EGF internalization may be regulated through similar mechanisms in other cell types. MATERIALS AND METHODSPreparation of Acini and Cell Culture. Pancreatic acini were prepared from fasted male Sprague-Dawley rats as reported (13). Freshly isolated acini were incubated for 60 min at 370C in Hepes-buffered Ringer solution that was titrated to pH 7.40, equilibrated with 100% oxygen (13), and resuspended in fresh Hepes/Ringer buffer (0.5-0.8 mg of protein per ml) for use in experiments. Derivation of Rat-1 fibroblasts (14), A-431 human vulvar carcinoma cells (12), and Swiss mouse 3T3 cells (15) has been described. All cell lines were propagated at 370C in a 5% C02/95% air atmosphere in Dulbecco's modified Eagle's medium supplemented with antibiotics and the following serum conditions: 10% newborn calf serum (3T3), 10% calf and 2% newborn calf serum (Rat-1), or 5% newborn calf and 2% fetal calf serum (A-431).Binding Studies. EGF was prepared from mouse submaxillary glands by the method of Savage and Cohen (16) and further purified by reverse-phase high-performance liquid chromatography (14). Biologically active 125I-EGF (14) and 125I-labeled insulin (1251-insulin) (17) were prepared with chloramine T. To measure binding in acini, 2-to 18-ml suspensions of cells were routinely incubated at 37°C with 1251_ EGF (23.4-53.0 ,uCi/,ug; 1 Ci = 37 GBq) or 125I-insulin (20.5 ,uCi/,ug). To separate bound and free hormone, 0.5-to 0.7-ml aliquots of...

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Section: Discussionmentioning

confidence: 99%

Cytosolic calcium regulates epidermal growth factor endocytosis in rat pancreas and cultured fibroblasts.

Korc¹,

Matrisian²,

Magun³

1984

Proc. Natl. Acad. Sci. U.S.A.

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“…Proglumide, another glutaramic acid derivative, that was developed in 1967 (Rovati et al 1967) has been known to have a CCK-antagonistic effect (Hahne et al 1981;Jensen et al 1983). However, we have recently reported that proglumide markedly increased the bile secretion and stimulated the basal pancreatic secretion via a mechanism independent of CCK receptor (Miyasaka et al 1987).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of CR-1409, a competitive inhibitor of cholecystokinin, on pancreatic exocrine secretion in the conscious rat.

Miyasaka

Nakamura

Funakoshi

et al. 1988

Tohoku J. Exp. Med.

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“…The first nonpeptide CCK antagonists-proglumide, dibutyryl cyclic GMP, and benzotript-exhibit very low in vitro potencies, which limits their in vivo utility (3). Furthermore, these agents lack a significant degree of selectivity for peripheral CCK receptors compared to brain CCK receptors or the closely related gastrin receptors, which mediate gastric acid secretion (4).…”

mentioning

confidence: 99%

Biochemical and pharmacological characterization of an extremely potent and selective nonpeptide cholecystokinin antagonist.

Chang¹,

Lotti²

1986

Proc. Natl. Acad. Sci. U.S.A.

439

174

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3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-IH-1,4-benzodiazepine-3-yl)-lH-indole-2-carboxamide (L-364,718) interacted in a competitive manner with rat pancreatic cholecystokinin (CCK) receptors as determined by Scatchard analysis of the specific binding of '21I-labeled CCK. The affinity of L-364,718 for both pancreatic (IC50, 81 pM) and gallbladder (IC50, 45 pM) CCK receptors in radioligand binding assays greatly exceeded that of other reported nonpeptide CCK antagonists and was similar to that of CCK itself. In vitro functional studies utilizing CCK-induced contractions of the isolated guinea pig ileum and colon further demonstrated that L-364,718 acts as a competitive CCK antagonist, which lacks agonist activity and has a similar high affinity in these tissues (pA2, 9.9). L-364,718 exhibited a very high selectivity for peripheral CCK receptors relative to brain CCK, gastrin, and various other peptide and nonpeptide receptors in both in vitro radioligand and isolated tissue assays.In vivo, low intravenous doses of L-364,718 (0.1 mg/kg) markedly antagonized the contractions of the guinea pig gallbladder produced by intravenous administration of CCK for at least 2 hr. Administered orally, L-364,718 (ED50, 0.04 mg/kg) was highly effective as an antagonist of CCK-induced inhibition of gastric emptying in mice. The biochemical and pharmacological properties of L-364,718-namely, very high affinity and selectivity for peripheral CCK receptors, longlasting in vivo efficacy, and oral bioavailability-makes this compound a powerful tool for investigating the physiological and pharmacological actions of CCK, and possibly its role in gastrointestinal disorders.

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Proglumide and benzotript: members of a different class of cholecystokinin receptor antagonists.

Cited by 176 publications

References 19 publications

Cytosolic calcium regulates epidermal growth factor endocytosis in rat pancreas and cultured fibroblasts.

Cytosolic calcium regulates epidermal growth factor endocytosis in rat pancreas and cultured fibroblasts.

Inhibitory effect of CR-1409, a competitive inhibitor of cholecystokinin, on pancreatic exocrine secretion in the conscious rat.

Biochemical and pharmacological characterization of an extremely potent and selective nonpeptide cholecystokinin antagonist.

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