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Keiji Miyata - One of the best experts on this subject based on the ideXlab platform.
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yf476 is a new potent and selective gastrin <B>CholecystokininB> B Receptor antagonist in vitro and in vivo
Alimentary Pharmacology & Therapeutics, 1997Co-Authors: Y. Takinami, Akito Nishida, H Yuki, Shinobu Akuzawa, A Uchida, Y Takemoto, Mitsuaki Ohta, Masato Satoh, Graeme Semple, Keiji MiyataAbstract:Background: We newly synthesized YF476 ((R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2′-pyridyl)-1H-1,4-Benzodiazepin-3-yl]-3-(3-methylamino-phenyl)urea) as a gastrin/<B>CholecystokininB>-B (CCK-B) Receptor antagonist. We investigated the pharmacological profile of YF476 in vitro and in vivo. Methods: We examined the Binding properties of YF476 to the rat Brain, cloned canine and cloned human gastrin/CCK-B Receptors, and the effect of YF476 on secretagogue-induced gastric acid secretion in rats and Heidenhain pouch dogs. Results: YF476 replaced the specific Binding of [125I]CCK-8 to the rat Brain, cloned canine and cloned human gastrin/CCK-B Receptors, with Ki values of 0.068, 0.62 and 0.19 nM, respectively. The affinity of YF476 for rat Brain gastrin/CCK-B Receptor was 4100-fold higher than that for rat pancreatic CCK-A Receptor. In anaesthetized rats, intravenous YF476 inhiBited pentagastrin-induced acid secretion with an ED50 value of 0.0086 μmol/kg, But did not affect histamine- and Bethanechol-induced acid secretion at a dose of 10 μmol/kg. In Heidenhain pouch dogs, intravenous and oral YF476 inhiBited pentagastrin-stimulated gastric acid secretion in a dose-dependent manner with ED50 values of 0.018 and 0.020 μmol/kg, respectively, But did not affect histamine-induced acid secretion. Conclusion: These results suggest that YF476 is an extremely potent and highly selective gastrin/CCK-B Receptor antagonist, and that the gastrin/CCK-B Receptor is not involved in histamine- or Bethanechol-induced gastric acid secretion in dogs or rats.
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YF476 is a new potent and selective gastrin/<B>CholecystokininB>‐B Receptor antagonist in vitro and in vivo
Alimentary Pharmacology & Therapeutics, 1997Co-Authors: Y. Takinami, Akito Nishida, H Yuki, Shinobu Akuzawa, A Uchida, Y Takemoto, Mitsuaki Ohta, Masato Satoh, Graeme Semple, Keiji MiyataAbstract:Background: We newly synthesized YF476 ((R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2′-pyridyl)-1H-1,4-Benzodiazepin-3-yl]-3-(3-methylamino-phenyl)urea) as a gastrin/<B>CholecystokininB>-B (CCK-B) Receptor antagonist. We investigated the pharmacological profile of YF476 in vitro and in vivo. Methods: We examined the Binding properties of YF476 to the rat Brain, cloned canine and cloned human gastrin/CCK-B Receptors, and the effect of YF476 on secretagogue-induced gastric acid secretion in rats and Heidenhain pouch dogs. Results: YF476 replaced the specific Binding of [125I]CCK-8 to the rat Brain, cloned canine and cloned human gastrin/CCK-B Receptors, with Ki values of 0.068, 0.62 and 0.19 nM, respectively. The affinity of YF476 for rat Brain gastrin/CCK-B Receptor was 4100-fold higher than that for rat pancreatic CCK-A Receptor. In anaesthetized rats, intravenous YF476 inhiBited pentagastrin-induced acid secretion with an ED50 value of 0.0086 μmol/kg, But did not affect histamine- and Bethanechol-induced acid secretion at a dose of 10 μmol/kg. In Heidenhain pouch dogs, intravenous and oral YF476 inhiBited pentagastrin-stimulated gastric acid secretion in a dose-dependent manner with ED50 values of 0.018 and 0.020 μmol/kg, respectively, But did not affect histamine-induced acid secretion. Conclusion: These results suggest that YF476 is an extremely potent and highly selective gastrin/CCK-B Receptor antagonist, and that the gastrin/CCK-B Receptor is not involved in histamine- or Bethanechol-induced gastric acid secretion in dogs or rats.
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Biological activity of analogues of ym022 novel 3 amino suBstituted phenyl urea derivatives of 1 4 Benzodiazepin 2 one as gastrin <B>CholecystokininB> B Receptor antagonists
Chemical & Pharmaceutical Bulletin, 1996Co-Authors: Masato Satoh, Akito Nishida, Shinobu Akuzawa, Keiji Miyata, Mitsuaki Ohta, Yoshinori Okamoto, Hiroyuki Koshio, Toshiyasu Mase, Graeme SempleAbstract:A series of (3-suBstituted phenyl)urea analogues of the potent gastrin/<B>CholecystokininB> (CCK)-B Receptor antagonist YM022 has Been prepared. Structure-activity relationship studies of this series suggested that a numBer of analogues retained good in vitro potency for gastrin/CCK-B Receptor. In particular, the (3-amino suBstituted phenyl)urea derivatives (10-12) were more potent inhiBitors of pentagastrin-induced gastric acid secretion in rats than YM022 on intraduodenal (i.d.) administration.
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YM022 [(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl- 1H-1,4-Benzodiazepin-3-yl]-3-(3-methylphenyl)urea], a potent and selective gastrin/<B>CholecystokininB>-B Receptor antagonist, prevents gastric and duodenal lesions in rats.
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Akito Nishida, Y. Takinami, H Yuki, A Kobayashi, Shinobu Akuzawa, Takeshi Kamato, Mayumi Yamano, Yukinori Nagakura, Keiji MiyataAbstract:We evaluated the effect of YM022 [(R)-1-[2,3-dihydro-1-(2'- methylphenacyl)-2-oxo-5-phenyl-1H-1,4-Benzodiazepin-3-yl]-3- (3-methylphenyl)urea], a potent and selective gastrin/<B>CholecystokininB>-B Receptor antagonist, on gastric acid secretion and gastric and duodenal lesions in rats. Oral YM022 (0.1-10 mumol/kg), famotidine (0.3-30 mumol/kg) and omeprazole (3-100 mumol/kg) dose-dependently suppressed acid secretion in pylorusligated rats with ED50 values of 0.83, 1.63 and 10.9 mumol/kg, respectively. YM022 (1-10 mumol/kg p.o.), famotidine (1-10 mumol/kg p.o.) and omeprazole (10-100 mumol/kg p.o.) prevented indomethacin-induced gastric lesions in a dose-related manner. The potency of YM022 was comparaBle to that of famotidine and was 8 times greater than that of omeprazole. YM022 and famotidine partially inhiBited gastric damage induced By water-immersion and restraint stress, whereas omeprazole aBolished these lesions. In an acidified ethanol-induced gastric injury model, all three drugs inhiBited the formation of erosions. The YM022 dosage required in this model was much greater than that required in the inhiBition of gastric acid. The inhiBitory effect of YM022 was partially reversed By indomethacin, indicating the involvement of a prostaglandin-mediated pathway. YM022 (3-100 mumol/kg p.o.), famotidine (1-30 mumol/kg p.o.) and omeprazole (3-100 mumol/kg p.o.) inhiBited mepirizole-induced duodenal ulcers. On the Basis of ED50 values, YM022 was 5 times less potent than famotidine and as potent as omeprazole against mepirizole-induced duodenal ulcers. These results suggest that YM022 possesses antisecretory and antiulcer activities that are as potent as those of famotidine in rats and that YM022 represents a useful therapeutic agent in the treatment of peptic ulcer disease.
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ym022 r 1 2 3 dihydro 1 2 methylphenacyl 2 oxo 5 phenyl 1h 1 4 Benzodiazepin 3 yl 3 3 methylphenyl urea a potent and selective gastrin <B>CholecystokininB> B Receptor antagonist prevents gastric and duodenal lesions in rats
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Akito Nishida, Y. Takinami, H Yuki, A Kobayashi, Shinobu Akuzawa, Takeshi Kamato, Mayumi Yamano, Yukinori Nagakura, Keiji MiyataAbstract:We evaluated the effect of YM022 [(R)-1-[2,3-dihydro-1-(2'- methylphenacyl)-2-oxo-5-phenyl-1H-1,4-Benzodiazepin-3-yl]-3- (3-methylphenyl)urea], a potent and selective gastrin/<B>CholecystokininB>-B Receptor antagonist, on gastric acid secretion and gastric and duodenal lesions in rats. Oral YM022 (0.1-10 mumol/kg), famotidine (0.3-30 mumol/kg) and omeprazole (3-100 mumol/kg) dose-dependently suppressed acid secretion in pylorusligated rats with ED50 values of 0.83, 1.63 and 10.9 mumol/kg, respectively. YM022 (1-10 mumol/kg p.o.), famotidine (1-10 mumol/kg p.o.) and omeprazole (10-100 mumol/kg p.o.) prevented indomethacin-induced gastric lesions in a dose-related manner. The potency of YM022 was comparaBle to that of famotidine and was 8 times greater than that of omeprazole. YM022 and famotidine partially inhiBited gastric damage induced By water-immersion and restraint stress, whereas omeprazole aBolished these lesions. In an acidified ethanol-induced gastric injury model, all three drugs inhiBited the formation of erosions. The YM022 dosage required in this model was much greater than that required in the inhiBition of gastric acid. The inhiBitory effect of YM022 was partially reversed By indomethacin, indicating the involvement of a prostaglandin-mediated pathway. YM022 (3-100 mumol/kg p.o.), famotidine (1-30 mumol/kg p.o.) and omeprazole (3-100 mumol/kg p.o.) inhiBited mepirizole-induced duodenal ulcers. On the Basis of ED50 values, YM022 was 5 times less potent than famotidine and as potent as omeprazole against mepirizole-induced duodenal ulcers. These results suggest that YM022 possesses antisecretory and antiulcer activities that are as potent as those of famotidine in rats and that YM022 represents a useful therapeutic agent in the treatment of peptic ulcer disease.
G E Martin - One of the best experts on this subject based on the ideXlab platform.
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rp 73870 a gastrin <B>CholecystokininB> B Receptor antagonist with potent anti ulcer activity in the rat
Journal of Pharmacology and Experimental Therapeutics, 1995Co-Authors: Charles E Pendley, Leo R Fitzpatrick, A J Capolino, Marjorie Davis, N J Esterline, A Jakubowska, Philippe Bertrand, Claude Guyon, Mariechristine Dubroeucq, G E MartinAbstract:RP 73870, the racemic potassium salt of (([N-(methoxy-3-phenyl)-N-(N-methyl-N-phenyl-carBamoylmethyl)- carBamoylmethyl]-3-ureido)-3-phenyl)-2-ethylsulfonate-(RS) is a potent, reversiBle antagonist of Both gastrin and <B>CholecystokininB>-B Receptors in guinea pig and rat tissues. This compound is a potent inhiBitor of pentagastrin-stimulated gastric acid secretion in the perfused rat stomach. RP 73870 also inhiBits Basal gastric acid secretion in the rat, although at doses higher than that required for inhiBition of pentagastrin-stimulated gastric acid secretion. RP 73870 is a potent inhiBitor of aspirin-induced gastric damage in the rat. In the prevention of aspirin-induced gastric damage, RP 73870, given p.o., was 10-fold less potent than when given i.v. RP 73870 was as potent as a H2 Receptor antagonist or proton pump inhiBitor in the prevention of cysteamine-induced duodenal ulcers in the rat. Relative to other gastrin/<B>CholecystokininB>-B antagonists, RP 73870 demonstrates greater affinity to gastrin Binding sites, and possesses a unique spectrum of in vivo Biological activities appropriate for an anti-ulcer indication.
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RP 73870, a gastrin/<B>CholecystokininB>-B Receptor antagonist with potent anti-ulcer activity in the rat.
Journal of Pharmacology and Experimental Therapeutics, 1995Co-Authors: Charles E Pendley, Leo R Fitzpatrick, A J Capolino, N J Esterline, A Jakubowska, Philippe Bertrand, Claude Guyon, Mariechristine Dubroeucq, Marjorie A. Davis, G E MartinAbstract:RP 73870, the racemic potassium salt of (([N-(methoxy-3-phenyl)-N-(N-methyl-N-phenyl-carBamoylmethyl)- carBamoylmethyl]-3-ureido)-3-phenyl)-2-ethylsulfonate-(RS) is a potent, reversiBle antagonist of Both gastrin and <B>CholecystokininB>-B Receptors in guinea pig and rat tissues. This compound is a potent inhiBitor of pentagastrin-stimulated gastric acid secretion in the perfused rat stomach. RP 73870 also inhiBits Basal gastric acid secretion in the rat, although at doses higher than that required for inhiBition of pentagastrin-stimulated gastric acid secretion. RP 73870 is a potent inhiBitor of aspirin-induced gastric damage in the rat. In the prevention of aspirin-induced gastric damage, RP 73870, given p.o., was 10-fold less potent than when given i.v. RP 73870 was as potent as a H2 Receptor antagonist or proton pump inhiBitor in the prevention of cysteamine-induced duodenal ulcers in the rat. Relative to other gastrin/<B>CholecystokininB>-B antagonists, RP 73870 demonstrates greater affinity to gastrin Binding sites, and possesses a unique spectrum of in vivo Biological activities appropriate for an anti-ulcer indication.
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the gastrin <B>CholecystokininB> B Receptor antagonist l 365 260 reduces Basal acid secretion and prevents gastrointestinal damage induced By aspirin ethanol and cysteamine in the rat
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: Charles E Pendley, Leo R Fitzpatrick, R W Ewing, B F Molino, G E MartinAbstract:L-365,260, a nonpeptide antagonist of gastrin/CCK-B Receptors, was evaluated in Receptor Binding, antisecretory and gastrointestinal damage assays. L-365,260 Binds potently and stereo-selectively to gastrin and CCK-B sites in guinea pig tissue. In contrast, L-365,260 Binds to the isolated canine parietal cell gastrin Receptor weakly, and without stereoselectivity. In the pylorus-ligated rat, low doses of L-365,260, given i.v., attenuated pentagastrin-stimulated acid secretion, whereas higher doses were required to inhiBit Both histamine-stimulated and Basal acid secretion. In an aspirin-induced gastric damage model, L-365,260 was 2.4-fold less potent than the standard histamine H2 antagonist cimetidine in preventing gastric damage when given i.v., and was 8.3-fold less potent than cimetidine when given p.o. Moreover, the ED50 value for L-365,260, given i.v., in prevention of aspirin-induced gastric damage (11.5 mg/kg) agreed well with its ED50 value for inhiBition of Basal acid secretion (12.6 mg/kg). At doses as great as 100 mg/kg p.o., neither L-365,260 nor cimetidine had an effect on ethanol-induced gastric damage. L-365,260, although p.o. less BioavailaBle relative to cimetidine in the aspirin gastric damage model, was as potent as cimetidine in the prevention of cysteamine-induced duodenal ulcers in the rat. We conclude that the gastrin/CCK-B Receptor antagonist L-365,260, at doses supramaximal for the inhiBition of pentagastrin-stimulated secretory responses in vivo, inhiBits gastrointestinal damage in models of peptic ulcer disease By an antisecretory mechanism of action.
Soichi Takiguchi - One of the best experts on this subject based on the ideXlab platform.
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enhanced gastric emptying of a liquid gastric load in mice lacking <B>CholecystokininB> B Receptor a study of cck a B and aB Receptor gene knockout mice
Journal of Gastroenterology, 2004Co-Authors: Kyoko Miyasaka, Minoru Ohta, Setsuko Kanai, Yuki Yoshida, Aki Nagata, Toshimitsu Matsui, Tetsuo Noda, Norikazu Sato, Atsuo Jimi, Soichi TakiguchiAbstract:Although <B>CholecystokininB> (CCK) has Been shown to inhiBit gastric emptying via CCK-A Receptors (CCK-ARs), the role of CCK-B Receptors (CCK-BRs) has not Been verified. We examined whether gastric emptying of a nonnutrient liquid load was modified in CCK-AR, BR, and ARBR gene knockout mice. A liquid gastric load prepared with phenol red was administered via an orogastric tuBe (0.15 ml/mouse). The animals were killed By decapitation, and gastric emptying was estimated at 10 and 30 min after ingestion. The effects of the sulfated form of CCK-8 (CCK-8S) and of graded doses of atropine were examined. In addition, a proton pump inhiBitor was administered to wild-type mice to examine the contriBution of gastric acid to emptying. Gastric emptying was significantly enhanced in mice lacking CCK-BR, as compared with wild-type and CCK-AR(−/−) mice. CCK-8S inhiBited gastric emptying in mice with CCK-AR, But not in mice without CCK-AR. A proton pump inhiBitor did not affect gastric emptying. Atropine dose dependently inhiBited gastric emptying in all genotypes. The thickness of smooth muscle was comparaBle for all genotypes. The gastric emptying of a nonnutrient liquid load was enhanced in mice without CCK-BR, although the precise mechanism is not known.
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Enhanced gastric emptying of a liquid gastric load in mice lacking <B>CholecystokininB>-B Receptor: a study of CCK-A,B, and AB Receptor gene knockout mice
Journal of Gastroenterology, 2004Co-Authors: Kyoko Miyasaka, Minoru Ohta, Setsuko Kanai, Yuki Yoshida, Aki Nagata, Toshimitsu Matsui, Tetsuo Noda, Norikazu Sato, Atsuo Jimi, Soichi TakiguchiAbstract:Although <B>CholecystokininB> (CCK) has Been shown to inhiBit gastric emptying via CCK-A Receptors (CCK-ARs), the role of CCK-B Receptors (CCK-BRs) has not Been verified. We examined whether gastric emptying of a nonnutrient liquid load was modified in CCK-AR, BR, and ARBR gene knockout mice. Methods A liquid gastric load prepared with phenol red was administered via an orogastric tuBe (0.15 ml/mouse). The animals were killed By decapitation, and gastric emptying was estimated at 10 and 30 min after ingestion. The effects of the sulfated form of CCK-8 (CCK-8S) and of graded doses of atropine were examined. In addition, a proton pump inhiBitor was administered to wild-type mice to examine the contriBution of gastric acid to emptying. Results Gastric emptying was significantly enhanced in mice lacking CCK-BR, as compared with wild-type and CCK-AR(−/−) mice. CCK-8S inhiBited gastric emptying in mice with CCK-AR, But not in mice without CCK-AR. A proton pump inhiBitor did not affect gastric emptying. Atropine dose dependently inhiBited gastric emptying in all genotypes. The thickness of smooth muscle was comparaBle for all genotypes. Conclusions The gastric emptying of a nonnutrient liquid load was enhanced in mice without CCK-BR, although the precise mechanism is not known.
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energy metaBolism and turnover are increased in mice lacking the <B>CholecystokininB> B Receptor
Journal of Nutrition, 2002Co-Authors: Kyoko Miyasaka, Mineko Ichikawa, Minoru Ohta, Setsuko Kanai, Yuki Yoshida, Masao Masuda, Aki Nagata, Toshimitsu Matsui, Tetsuo Noda, Soichi TakiguchiAbstract:: <B>CholecystokininB> (CCK) is an important gastrointestinal hormone as well as a neurotransmitter. Two types of CCK Receptors, types A and B, have Been identified. The CCK-A Receptor is involved in satiety, food intake and Behavior, whereas the B Receptor is involved in anxiety. We recently produced CCK-A, -B and AB Receptor knockout mice to study the role of these Receptors in energy metaBolism. Daily energy intake and expenditure were significantly greater in CCK-BR(-/-) and CCK-AR(-/-)BR(-/-) mice than CCK-AR(-/-) and wild-type [CCK-AR(+/+)BR(+/+)] mice. Relative liver and kidney weights (g/kg Body) were significantly greater in CCK-AR(-/-)BR(-/-) mice than in wild-type mice. Energy metaBolism and energy turnover were increased in mice with a disruption of the CCK-BR gene, although the underlying mechanism is unknown.
Alain Eschalier - One of the best experts on this subject based on the ideXlab platform.
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enhancement of the effects of a complete inhiBitor of enkephalin cataBolizing enzymes rB 101 By a <B>CholecystokininB> B Receptor antagonist in diaBetic rats
British Journal of Pharmacology, 2001Co-Authors: Marieange Coudoreciviale, Bernard P Roques, M Boucher, Murielle Meen, Marieclaude Fourniezaluski, Alain EschalierAbstract:RB 101, a complete inhiBitor of enkephalin-cataBolizing enzymes, has Been previously shown to produce antinociception in normal rats after systemic administration. Moreover, its coadministration with a <B>CholecystokininB>-B (CCK-B) Receptor antagonist has Been shown to strongly enhance its antinociceptive effect in normal rats. In this work, we determined whether RB 101 was aBle to reduce hyperalgesia and allodynia in diaBetic rats, a model of neuropathic pain. The type of opioid Receptors (μ or δ) involved was determined using naloxone and naltrindole, respectively, and the interactions Between endogenous enkephalins and CCK on nociception control was investigated using coadministration of RB 101 and the CCK-B Receptor antagonist CI-988. RB 101 suppressed mechanical hyperalgesia (paw pressure-induced vocalization test), partially alleviated mechanical allodynia (von Frey hair test), and was ineffective in thermal allodynia (tail immersion test). The analgesic effect was completely cancelled By naloxone or naltrindole, suggesting that is requires the availaBility of μ- and/or δ-opioid Receptors. The comBination of an inactive dose of CI-988 with the lowest effective dose of RB 101 resulted in a stronger increase in the vocalization threshold comparatively to RB 101 alone. The present study demonstrates that the antinociception generated By RB 101 induced By elevation of extracellular levels of endogenous enkephalins, can Be extended to neuropathic pain in diaBetic rats and that Blockade of CCK-B Receptors potentiated antinociceptive effects elicited By RB 101. British Journal of Pharmacology (2001) 133, 179–185; doi:10.1038/sj.Bjp.0704059
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spinal effect of the <B>CholecystokininB> B Receptor antagonist ci 988 on hyperalgesia allodynia and morphine induced analgesia in diaBetic and mononeuropathic rats
Pain, 2000Co-Authors: Marieange Coudoreciviale, Christine Courteix, J Fialip, M Boucher, Alain EschalierAbstract:ABstract Since evidence points to the involvement of <B>CholecystokininB> (CCK) in nociception, we examined the effect of intrathecal CI-988, an antagonist of the CCK-B Receptors, on mechanical hyperalgesia and allodynia in normal, mononeuropathic and diaBetic rats,. Owing to the anti-opioid activity of CCK, it has Been suggested that hyperactivity in the spinal CCK system is responsiBle for the low sensitivity of neuropathic pain to opioids. We therefore also evaluated the effect of the comBination of i.t. CI-988+i.v. morphine on mechanical hyperalgesia in diaBetic and mononeuropathic rats using isoBolographic analysis. Although ineffective in normal rats, CI-988 induced antinociceptive effects in diaBetic (290±20 g with a cut-off of 750 g) and mononeuropathic (117±16 g; cut-off 750 g) rats, suggesting an involvement of the CCKergic system in neurogenic pain conditions. The comBination of CI-988 and morphine showed a superadditive interaction in the diaBetic rats only (477±16 g; cut-off 750 g), in comparison with the antinociceptive effect of each drug. In addition, CI-988 exhiBited a weak anti-allodynic effect in mononeuropathic rats, and no anti-allodynic effect in diaBetic rats. These results show the CCK-B Receptor Blockade-mediated antinociceptive effects and reveals the antinociceptive action of morphine in diaBetic rats after CCKergic system inhiBition.
Akito Nishida - One of the best experts on this subject based on the ideXlab platform.
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yf476 is a new potent and selective gastrin <B>CholecystokininB> B Receptor antagonist in vitro and in vivo
Alimentary Pharmacology & Therapeutics, 1997Co-Authors: Y. Takinami, Akito Nishida, H Yuki, Shinobu Akuzawa, A Uchida, Y Takemoto, Mitsuaki Ohta, Masato Satoh, Graeme Semple, Keiji MiyataAbstract:Background: We newly synthesized YF476 ((R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2′-pyridyl)-1H-1,4-Benzodiazepin-3-yl]-3-(3-methylamino-phenyl)urea) as a gastrin/<B>CholecystokininB>-B (CCK-B) Receptor antagonist. We investigated the pharmacological profile of YF476 in vitro and in vivo. Methods: We examined the Binding properties of YF476 to the rat Brain, cloned canine and cloned human gastrin/CCK-B Receptors, and the effect of YF476 on secretagogue-induced gastric acid secretion in rats and Heidenhain pouch dogs. Results: YF476 replaced the specific Binding of [125I]CCK-8 to the rat Brain, cloned canine and cloned human gastrin/CCK-B Receptors, with Ki values of 0.068, 0.62 and 0.19 nM, respectively. The affinity of YF476 for rat Brain gastrin/CCK-B Receptor was 4100-fold higher than that for rat pancreatic CCK-A Receptor. In anaesthetized rats, intravenous YF476 inhiBited pentagastrin-induced acid secretion with an ED50 value of 0.0086 μmol/kg, But did not affect histamine- and Bethanechol-induced acid secretion at a dose of 10 μmol/kg. In Heidenhain pouch dogs, intravenous and oral YF476 inhiBited pentagastrin-stimulated gastric acid secretion in a dose-dependent manner with ED50 values of 0.018 and 0.020 μmol/kg, respectively, But did not affect histamine-induced acid secretion. Conclusion: These results suggest that YF476 is an extremely potent and highly selective gastrin/CCK-B Receptor antagonist, and that the gastrin/CCK-B Receptor is not involved in histamine- or Bethanechol-induced gastric acid secretion in dogs or rats.
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YF476 is a new potent and selective gastrin/<B>CholecystokininB>‐B Receptor antagonist in vitro and in vivo
Alimentary Pharmacology & Therapeutics, 1997Co-Authors: Y. Takinami, Akito Nishida, H Yuki, Shinobu Akuzawa, A Uchida, Y Takemoto, Mitsuaki Ohta, Masato Satoh, Graeme Semple, Keiji MiyataAbstract:Background: We newly synthesized YF476 ((R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2′-pyridyl)-1H-1,4-Benzodiazepin-3-yl]-3-(3-methylamino-phenyl)urea) as a gastrin/<B>CholecystokininB>-B (CCK-B) Receptor antagonist. We investigated the pharmacological profile of YF476 in vitro and in vivo. Methods: We examined the Binding properties of YF476 to the rat Brain, cloned canine and cloned human gastrin/CCK-B Receptors, and the effect of YF476 on secretagogue-induced gastric acid secretion in rats and Heidenhain pouch dogs. Results: YF476 replaced the specific Binding of [125I]CCK-8 to the rat Brain, cloned canine and cloned human gastrin/CCK-B Receptors, with Ki values of 0.068, 0.62 and 0.19 nM, respectively. The affinity of YF476 for rat Brain gastrin/CCK-B Receptor was 4100-fold higher than that for rat pancreatic CCK-A Receptor. In anaesthetized rats, intravenous YF476 inhiBited pentagastrin-induced acid secretion with an ED50 value of 0.0086 μmol/kg, But did not affect histamine- and Bethanechol-induced acid secretion at a dose of 10 μmol/kg. In Heidenhain pouch dogs, intravenous and oral YF476 inhiBited pentagastrin-stimulated gastric acid secretion in a dose-dependent manner with ED50 values of 0.018 and 0.020 μmol/kg, respectively, But did not affect histamine-induced acid secretion. Conclusion: These results suggest that YF476 is an extremely potent and highly selective gastrin/CCK-B Receptor antagonist, and that the gastrin/CCK-B Receptor is not involved in histamine- or Bethanechol-induced gastric acid secretion in dogs or rats.
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Biological activity of analogues of ym022 novel 3 amino suBstituted phenyl urea derivatives of 1 4 Benzodiazepin 2 one as gastrin <B>CholecystokininB> B Receptor antagonists
Chemical & Pharmaceutical Bulletin, 1996Co-Authors: Masato Satoh, Akito Nishida, Shinobu Akuzawa, Keiji Miyata, Mitsuaki Ohta, Yoshinori Okamoto, Hiroyuki Koshio, Toshiyasu Mase, Graeme SempleAbstract:A series of (3-suBstituted phenyl)urea analogues of the potent gastrin/<B>CholecystokininB> (CCK)-B Receptor antagonist YM022 has Been prepared. Structure-activity relationship studies of this series suggested that a numBer of analogues retained good in vitro potency for gastrin/CCK-B Receptor. In particular, the (3-amino suBstituted phenyl)urea derivatives (10-12) were more potent inhiBitors of pentagastrin-induced gastric acid secretion in rats than YM022 on intraduodenal (i.d.) administration.
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YM022 [(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl- 1H-1,4-Benzodiazepin-3-yl]-3-(3-methylphenyl)urea], a potent and selective gastrin/<B>CholecystokininB>-B Receptor antagonist, prevents gastric and duodenal lesions in rats.
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Akito Nishida, Y. Takinami, H Yuki, A Kobayashi, Shinobu Akuzawa, Takeshi Kamato, Mayumi Yamano, Yukinori Nagakura, Keiji MiyataAbstract:We evaluated the effect of YM022 [(R)-1-[2,3-dihydro-1-(2'- methylphenacyl)-2-oxo-5-phenyl-1H-1,4-Benzodiazepin-3-yl]-3- (3-methylphenyl)urea], a potent and selective gastrin/<B>CholecystokininB>-B Receptor antagonist, on gastric acid secretion and gastric and duodenal lesions in rats. Oral YM022 (0.1-10 mumol/kg), famotidine (0.3-30 mumol/kg) and omeprazole (3-100 mumol/kg) dose-dependently suppressed acid secretion in pylorusligated rats with ED50 values of 0.83, 1.63 and 10.9 mumol/kg, respectively. YM022 (1-10 mumol/kg p.o.), famotidine (1-10 mumol/kg p.o.) and omeprazole (10-100 mumol/kg p.o.) prevented indomethacin-induced gastric lesions in a dose-related manner. The potency of YM022 was comparaBle to that of famotidine and was 8 times greater than that of omeprazole. YM022 and famotidine partially inhiBited gastric damage induced By water-immersion and restraint stress, whereas omeprazole aBolished these lesions. In an acidified ethanol-induced gastric injury model, all three drugs inhiBited the formation of erosions. The YM022 dosage required in this model was much greater than that required in the inhiBition of gastric acid. The inhiBitory effect of YM022 was partially reversed By indomethacin, indicating the involvement of a prostaglandin-mediated pathway. YM022 (3-100 mumol/kg p.o.), famotidine (1-30 mumol/kg p.o.) and omeprazole (3-100 mumol/kg p.o.) inhiBited mepirizole-induced duodenal ulcers. On the Basis of ED50 values, YM022 was 5 times less potent than famotidine and as potent as omeprazole against mepirizole-induced duodenal ulcers. These results suggest that YM022 possesses antisecretory and antiulcer activities that are as potent as those of famotidine in rats and that YM022 represents a useful therapeutic agent in the treatment of peptic ulcer disease.
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ym022 r 1 2 3 dihydro 1 2 methylphenacyl 2 oxo 5 phenyl 1h 1 4 Benzodiazepin 3 yl 3 3 methylphenyl urea a potent and selective gastrin <B>CholecystokininB> B Receptor antagonist prevents gastric and duodenal lesions in rats
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Akito Nishida, Y. Takinami, H Yuki, A Kobayashi, Shinobu Akuzawa, Takeshi Kamato, Mayumi Yamano, Yukinori Nagakura, Keiji MiyataAbstract:We evaluated the effect of YM022 [(R)-1-[2,3-dihydro-1-(2'- methylphenacyl)-2-oxo-5-phenyl-1H-1,4-Benzodiazepin-3-yl]-3- (3-methylphenyl)urea], a potent and selective gastrin/<B>CholecystokininB>-B Receptor antagonist, on gastric acid secretion and gastric and duodenal lesions in rats. Oral YM022 (0.1-10 mumol/kg), famotidine (0.3-30 mumol/kg) and omeprazole (3-100 mumol/kg) dose-dependently suppressed acid secretion in pylorusligated rats with ED50 values of 0.83, 1.63 and 10.9 mumol/kg, respectively. YM022 (1-10 mumol/kg p.o.), famotidine (1-10 mumol/kg p.o.) and omeprazole (10-100 mumol/kg p.o.) prevented indomethacin-induced gastric lesions in a dose-related manner. The potency of YM022 was comparaBle to that of famotidine and was 8 times greater than that of omeprazole. YM022 and famotidine partially inhiBited gastric damage induced By water-immersion and restraint stress, whereas omeprazole aBolished these lesions. In an acidified ethanol-induced gastric injury model, all three drugs inhiBited the formation of erosions. The YM022 dosage required in this model was much greater than that required in the inhiBition of gastric acid. The inhiBitory effect of YM022 was partially reversed By indomethacin, indicating the involvement of a prostaglandin-mediated pathway. YM022 (3-100 mumol/kg p.o.), famotidine (1-30 mumol/kg p.o.) and omeprazole (3-100 mumol/kg p.o.) inhiBited mepirizole-induced duodenal ulcers. On the Basis of ED50 values, YM022 was 5 times less potent than famotidine and as potent as omeprazole against mepirizole-induced duodenal ulcers. These results suggest that YM022 possesses antisecretory and antiulcer activities that are as potent as those of famotidine in rats and that YM022 represents a useful therapeutic agent in the treatment of peptic ulcer disease.