Antispasdomic activity on the gallbladder of the mouse of CR 1409 (Lorglumide) a potent antagonist of peripheral CCK

Makovec, Francesco; Bani, Massimo; Cereda, Roberta; Chisté, Renan Campos; Pacini, Maria Irene; Revel, Laura; Rovati, Lucio C.

doi:10.1016/0031-6989(87)90031-2

Cited by 23 publications

(15 citation statements)

References 7 publications

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“…We found a distinct acceleration of gastric meal emptying during the infusion of the highly potent and specific CCK blocker loxiglumide. Our results confirm previous animal [8,[24][25][26][27][28][29][30] and human [19,31] studies using loxiglumide and its related compounds proglumide and lorglumide [8,19,[24][25][26][27]31] as well as other types of CCK antagonists such as MK-329 [28][29][30] demonstrating a marked acceleration of the gastric emptying rate by CCK blockade. The only two negative studies [32,33] used a solidliquid meal while we employed a liquid meal.…”

Section: Discussionsupporting

confidence: 89%

Physiological role of cholecystokinin on postprandial insulin secretion and gastric meal emptying in man. Studies with the cholecystokinin receptor antagonist loxiglumide

et al. 1991

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Cholecystokinin was previously proposed to play an important role in the regulation of postprandial insulin secretion either indirectly, by inhibiting gastric meal emptying, or directly, by acting as an incretin promoting the release of insulin. The aim of this investigation was therefore to clarify the role of endogenous cholecystokinin in the regulation of insulin release and gastric emptying applying the highly potent and specific cholecystokinin receptor antagonist loxiglumide. Five healthy volunteers were examined after an overnight fast. Gastric meal emptying was measured by the double indicator technique using a multiple lumen tube in the duodenum and 99mTc-diethylenetriamine pentaacetate as a meal marker and polyethylene glycol 4000 as a duodenal perfusion marker. Postprandial insulin, C-peptide, cholecystokinin and glucose levels were measured after ingestion of two isocaloric meals of a) Ensure (containing fat, protein and glucose), and b) a pure glucose meal (1.11 mol/l). The meals were given either with an intravenous infusion of loxiglumide (22 mumol.kg-1.h-1) or placebo. The infusion of loxiglumide markedly accelerated the gastric emptying of the mixed meal (area under curve, 5576 +/- 352 min vs 3498 +/- 109 min; p less than 0.001) and the pure glucose meal (area under curve 5662 +/- 537 min vs 3551 +/- 534 min; p less than 0.05). Simultaneously, loxiglumide induced a more rapid rise in postprandial insulin levels after both meals resulting in significantly higher (p less than 0.05) insulin levels during the first postprandial hour, but similar insulin levels in the second postprandial hour. Accordingly, we found a close correlation between meal emptying and insulin release (r = 0.748, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 89%

Physiological role of cholecystokinin on postprandial insulin secretion and gastric meal emptying in man. Studies with the cholecystokinin receptor antagonist loxiglumide

et al. 1991

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“…Therefore, in addition we evaluated the effect of lorglumide (CR 1409). a new glutaramic acid derivative endowed with potent (its pA2 ranged from 6.7 to 7.8) and selective CCK-antagonistic activity (Baftho et Makovec et al, 1985Makovec et al, , 1986Makovec et al, , 1987, which was shown to affect exocrine pancreatic secretion in vitro (Jensen et al, 1986;Niederau et al, 1986). According to the recently proposed classification (Dourish and Hill, 1987), the selectivity of lorglu-mide for CCKA (peripheral) versus CCKB (central) receptors is more than 1 O00 times higher than that of proglumide.…”

Section: Introductionmentioning

confidence: 99%

Pancreatic Secretory and Trophic Response to Caerulein in Rats: Effect of Proglumide and Lorglumide

Varga

Papp

Scarpignato

1989

Fundamemntal Clinical Pharma

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The effect of proglumide and lorglumide, two CCK-receptor antagonists, on caerulein-induced pancreatic secretion and growth was studied in the rat. In anaesthetised animals, caerulein (1 microgram/kg) significantly increased the volume of pancreatic juice and protein output. Lorglumide (5 and 10 mg/kg), administered intraperitoneally 15 min before stimulation, reduced peptide-induced pancreatic exocrine secretion. By contrast, proglumide (100 and 400 mg/kg) was completely ineffective. In experiments dealing with the trophic effect of caerulein, both drugs were administered alone or combined with the peptide (1 microgram/kg) 3 times daily for 5 d. Saline-treated rats served as controls. At the end of the experiment, rats were sacrificed, and growth and composition of pancreatic tissue were determined. Pretreatment of the animals with either proglumide or lorglumide did not affect pancreatic size and composition. Caerulein increased the weight of the pancreas, the total pancreatic protein, trypsin, amylase, and DNA content. After pretreatment with proglumide, all these parameters were not significantly different from those obtained with caerulein alone. In contrast, when lorglumide was given together with caerulein, it significantly reduced caerulein-induced pancreatic growth and decreased enzymatic protein content of the gland. These results show that lorglumide is a much more potent and effective CCK-receptor antagonist than proglumide. Its ability to antagonize the pancreatic secretory and trophic action of a CCK-analogue (i.e. caerulein) supports the view that these physiological actions of CCK are mediated through an interaction of the hormone with specific receptors.

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“…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). Recently, asperlicin (4) and a proglumide derivative designated compound 16 (5) have been reported, which have improved potency and, for asperlicin, greater selectivity for peripheral CCK receptors than previous agents.…”

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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Antispasdomic activity on the gallbladder of the mouse of CR 1409 (Lorglumide) a potent antagonist of peripheral CCK

Cited by 23 publications

References 7 publications

Physiological role of cholecystokinin on postprandial insulin secretion and gastric meal emptying in man. Studies with the cholecystokinin receptor antagonist loxiglumide

Physiological role of cholecystokinin on postprandial insulin secretion and gastric meal emptying in man. Studies with the cholecystokinin receptor antagonist loxiglumide

Pancreatic Secretory and Trophic Response to Caerulein in Rats: Effect of Proglumide and Lorglumide

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

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