Effect of T-0632, a CholecystokininA Receptor Antagonist, on Experimental Acute Pancreatitis.

Taniguchi, Hiroyuki; Yomota, Eiji; Kume, Eisuke; Shikano, Toshirou; Endo, Toshio; Nagasaki, Masaaki

doi:10.1254/jjp.73.105

Cited by 12 publications

(7 citation statements)

References 26 publications

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“…High CCK levels have been however reported in patients with gallstone pancreatitis [51]. In this model, common BPDL caused an increase in plasma amylase activity, in line with most of previous data [44,47,50]. The protective effect of devazepide was also in keeping with previous studies [52,53], although other investigators have described the lack of effect of this CCK 1 receptor antagonist on hyperamylasemia [50].…”

Section: Discussionsupporting

confidence: 91%

“…In the present study, the new compound IQM-97,423 was tested in two experimental models of acute pancreatitis, induced by supramaximal doses of the CCK agonist cerulein or by combined bile and pancreatic duct obstruction. The first model mimics human edematous pancreatitis caused by alcohol abuse while the second one is considered a model of human pancreatitis caused by gallstones or pancreatic stones [44].…”

Section: Discussionmentioning

confidence: 99%

“…Combined bile and pancreatic duct obstruction induces acute pancreatitis and increases circulating CCK [35] by excluding bile and pancreatic juice from the gut. The contribution of CCK to common BPDL-induced acute pancreatitis is not clear since the effects of CCK 1 receptor antagonists on this model are controversial [44,50]. High CCK levels have been however reported in patients with gallstone pancreatitis [51].…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological Study of IQM-97,423, a Potent and Selective CCK<sub>1</sub> Receptor Antagonist with Protective Effect in Experimental Acute Pancreatitis

et al. 2004

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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 CCK_8S-stimulated α-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 CCK_8S 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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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Pharmacological Study of IQM-97,423, a Potent and Selective CCK<sub>1</sub> Receptor Antagonist with Protective Effect in Experimental Acute Pancreatitis

et al. 2004

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“…Third, OLETF rats lacking CCK1R expression develop less severe pancreatitis in several experimental models [90,91]. Fourth, administration of CCK1R antagonists reduced the severity of pancreatitis in most [87,89,[92][93][94][95][96][97][98][99] but not all [100][101][102] animal studies of experimental pancreatitis. One study [102] even showed that the specific CCK1R antagonist L-364,718 ( Fig.…”

Section: Iib2b1 Cck1r In Acute Pancreatitisgeneralmentioning

confidence: 99%

Role of CCK/Gastrin Receptors in Gastrointestinal/Metabolic Diseases and Results of Human Studies Using Gastrin/CCK Receptor Agonists/Antagonists in these Diseases

Berna

Jensen

2007

CTMC

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In this paper, the established and possible roles of CCK1 and CCK2 receptors in gastrointestinal (GI) and metabolic diseases are reviewed and available results from human agonist/antagonist studies are discussed. While there is evidence for the involvement of CCK1R in numerous diseases including pancreatic disorders, motility disorders, tumor growth, regulation of satiety and a number of CCK-deficient states, the role of CCK1R in these conditions is not clearly defined. There are encouraging data from several clinical studies of CCK1R antagonists in some of these conditions, but their role as therapeutic agents remains unclear. The role of CCK2R in physiological (atrophic gastritis, pernicious anemia) and pathological (Zollinger-Ellison syndrome) hypergastrinemic states, its effects on the gastric mucosa (ECL cell hyperplasia, carcinoids, parietal cell mass) and its role in acid-peptic disorders are clearly defined. Furthermore, recent studies point to a possible role for CCK2R in a number of GI malignancies. Current data from human studies of CCK2R antagonists are presented and their potential role in the treatment of these conditions reviewed. Furthermore, the role of CCK2 receptors as targets for medical imaging is discussed.

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“…In this study, the effects of this CCK 1 antagonist were more selective for the pancreas than for the gall bladder. 264 In different models of experimental acute pancreatitis, T-0632 has shown preventive effects by oral or intraduodenal administration, 265,266 and has been studied in Phase I clinical trials for the treatment of pancreatic disorders, although results of these studies have not been reported.…”

Section: K Indol-2-one-based Cck Antagonistsmentioning

confidence: 99%

Cholecystokinin antagonists: Pharmacological and therapeutic potential

Herranz

2003

Medicinal Research Reviews

168

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Cholecystokinin (CCK) is a regulatory peptide hormone, predominantly found in the gastrointestinal tract, and a neurotransmitter present throughout the nervous system. In the gastrointestinal system CCK regulates motility, pancreatic enzyme secretion, gastric emptying, and gastric acid secretion. In the nervous system CCK is involved in anxiogenesis, satiety, nociception, and memory and learning processes. Moreover, CCK interacts with other neurotransmitters in some areas of the CNS. The biological effects of CCK are mediated by two specific G protein coupled receptor subtypes, termed CCK(1) and CCK(2). Over the past fifteen years the search of CCK receptor ligands has evolved from the initial CCK structure derived peptides towards peptidomimetic or non-peptide agonists and antagonists with improved pharmacokinetic profile. This research has provided a broad assortment of potent and selective CCK(1) and CCK(2) antagonists of diverse chemical structure. These antagonists have been discovered through optimization programs of lead compounds which were designed based on the structures of the C-terminal tetrapeptide, CCK-4, or the non-peptide natural compound, asperlicin, or derived from random screening programs. This review covers the main pharmacological and therapeutic aspects of these CCK(1) and CCK(2) antagonist. CCK(1) antagonists might have therapeutic potential for the treatment of pancreatic disorders and as prokinetics for the treatment of gastroesophageal reflux disease, bowel disorders, and gastroparesis. On the other hand, CCK(2) antagonists might have application for the treatment of gastric acid secretion and anxiety disorders.

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Effect of T-0632, a CholecystokininA Receptor Antagonist, on Experimental Acute Pancreatitis.

Cited by 12 publications

References 26 publications

Pharmacological Study of IQM-97,423, a Potent and Selective CCK<sub>1</sub> Receptor Antagonist with Protective Effect in Experimental Acute Pancreatitis

Pharmacological Study of IQM-97,423, a Potent and Selective CCK<sub>1</sub> Receptor Antagonist with Protective Effect in Experimental Acute Pancreatitis

Role of CCK/Gastrin Receptors in Gastrointestinal/Metabolic Diseases and Results of Human Studies Using Gastrin/CCK Receptor Agonists/Antagonists in these Diseases

Cholecystokinin antagonists: Pharmacological and therapeutic potential

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