Gastrin receptor antagonist YM022 prevents hypersecretion after long-term acid suppression

Nishida, Akito; Kobayashi-Uchida, A; Akuzawa, Shinobu; Takinami, Yusuke; Shishido, T.; Kamato, Takeshi; Ito, Hiroya; Yamano, Michiyo; Yuki, Hidenobu; Nagakura, Yukinori

doi:10.1152/ajpgi.1995.269.5.g699

Cited by 18 publications

(21 citation statements)

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“…166 Moreover, YM022, given orally, was able to practically inhibit gastric damage induced by restraint stress, and inhibited the hypersecretion observed following cessation of omeprazole treatment. 167 These results supported the assertion that this compound may have a role as an alternative anti-ulcer therapy devoid of the risk in relapse, and promoted YM022 to Phase I clinical studies. Greater aqueous solubility and oral bioavailability was achieved by the introduction of basic groups, by replacing either the 5-phenyl group by a 2-pyridyl substituent, or the 3-methyl group of the aryl urea moiety by a methylamino group as in YF476 168 (31, also known as YM-220).…”

Section: Cck 2 Receptor Antagonistssupporting

confidence: 58%

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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Section: Cck 2 Receptor Antagonistssupporting

confidence: 58%

Cholecystokinin antagonists: Pharmacological and therapeutic potential

Herranz

2003

Medicinal Research Reviews

168

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“…This conclusion was drawn already by Eissele et al (1992), using the tryptophan dipeptoid PD 136450 (CAM 1189) as CCK 2 receptor antagonist. Nishida et al (1995) used YM022 to show that CCK 2 receptor blockade prevented the omeprazole-induced activation of oxyntic mucosal HDC, a finding that we could confirm. In contrast, both YM022 and YF476 are powerful and selective antagonists for the CCK 2 receptor (Ding et al 1997;Takinami et al 1997;Lindström et al 1999).…”

Section: Effect Of Cck 2 Receptor Blockade On Ecl-cell Morphologymentioning

confidence: 56%

Effect of cholecystokinin-2 receptor blockade on rat stomach ECL cells

Chen¹,

Zhao²,

Norlén³

et al. 2000

Cell and Tissue Research

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The ECL cells in the oxyntic mucosa of rat stomach produce histamine and chromogranin A-derived peptides such as pancreastatin. The cells respond to gastrin via cholecystokinin-2 (CCK2) receptors. A CCK2 receptor blockade was induced by treatment (for up to 8 weeks) with two receptor antagonists, YM022 and YF476. Changes in ECL-cell morphology were examined by immunocytochemistry and electron microscopy, while changes in ECL cell-related biochemical parameters were monitored by measuring serum pancreastatin and oxyntic mucosal pancreastatin, and histamine concentrations, and histidine decarboxylase (HDC) activity. The CCK2 receptor blockade reduced the ECL-cell density only marginally, if at all, but transformed the ECL cells from slender, elongated cells with prominent projections to small, spherical cells without projections. The Golgi complex and the rough endoplasmic reticulum were diminished. Secretory vesicles were greatly reduced in volume density in the trans Golgi area. Circulating pancreastatin concentration and oxyntic mucosal HDC activity were lowered within a few hours. Oxyntic mucosal histamine and pancreastatin concentrations were reduced only gradually. The CCK2 receptor blockade was found to prevent the effects of omeprazole-evoked hypergastrinaemia on the ECL-cell activity and density. In conclusion, gastrin, acting on CCK2 receptors, is needed to maintain the shape, size and activity of the ECL cells, but not for maintaining the ECL-cell population.

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“…As a control, we also assessed the drug effects on plasma gastrin levels and on cell proliferation in the normal oxyntic mucosa (10,11). Omeprazole and YF-476 caused approximately a sevenfold increase in plasma gastrin levels and a slight, but significant, increase in cell proliferation of the oxyntic mucosa.…”

Section: Discussionmentioning

confidence: 99%