KDR-5169, a new gastrointestinal prokinetic agent, enhances gastric contractile and emptying activities in dogs and rats

KDR-5169, a new gastrointestinal prokinetic agent, enhances gastric contractile and emptying... KDR-5169, 4-amino-5-chloro- N -(1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl)-2-(2-hydroxyethoxy)benzamide hydrochloride dihydrate, is a new prokinetic with a dual action, i.e., stimulation of the 5-HT 4 receptor and antagonism of the dopamine D2 receptor. In this study, we determined in vitro activities of KDR-5169 towards both receptors and demonstrated the effect of the compound on gastrointestinal motor activity in conscious dogs and rats. In dogs, intravenous KDR-5169 stimulated upper gastrointestinal motility in the fasting state and also eliminated the depressive effect of 3,4-dihydroxyphenylalanine ( l -DOPA) on this motility in the postprandial state. The effect of KDR-5169 on gastric emptying was further characterized by the use of three rat gastroparesis models (dopamine D2 receptor agonist (quinpirol)-, abdominal surgery-, or combined-situation-induced). Domperidone (a dopamine D2 receptor antagonist) was effective in the quinpirol-delay and combination-delay models, and cisapride and mosapride (5-HT 4 receptor agonists) were effective in the surgery-delay model. Only KDR-5169 eliminated the delay of gastric emptying in all three models. In addition, KDR-5169 accelerated emptying to above the normal level in the combination-delay model. These results suggest that KDR-5169 would be effective in various types of gastric ileus caused by different mechanisms. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Pharmacology Elsevier

KDR-5169, a new gastrointestinal prokinetic agent, enhances gastric contractile and emptying activities in dogs and rats

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Publisher
Elsevier
Copyright
Copyright © 2002 Elsevier Science B.V.
ISSN
0014-2999
D.O.I.
10.1016/S0014-2999(01)01543-6
Publisher site
See Article on Publisher Site

Abstract

KDR-5169, 4-amino-5-chloro- N -(1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl)-2-(2-hydroxyethoxy)benzamide hydrochloride dihydrate, is a new prokinetic with a dual action, i.e., stimulation of the 5-HT 4 receptor and antagonism of the dopamine D2 receptor. In this study, we determined in vitro activities of KDR-5169 towards both receptors and demonstrated the effect of the compound on gastrointestinal motor activity in conscious dogs and rats. In dogs, intravenous KDR-5169 stimulated upper gastrointestinal motility in the fasting state and also eliminated the depressive effect of 3,4-dihydroxyphenylalanine ( l -DOPA) on this motility in the postprandial state. The effect of KDR-5169 on gastric emptying was further characterized by the use of three rat gastroparesis models (dopamine D2 receptor agonist (quinpirol)-, abdominal surgery-, or combined-situation-induced). Domperidone (a dopamine D2 receptor antagonist) was effective in the quinpirol-delay and combination-delay models, and cisapride and mosapride (5-HT 4 receptor agonists) were effective in the surgery-delay model. Only KDR-5169 eliminated the delay of gastric emptying in all three models. In addition, KDR-5169 accelerated emptying to above the normal level in the combination-delay model. These results suggest that KDR-5169 would be effective in various types of gastric ileus caused by different mechanisms.

Journal

European Journal of PharmacologyElsevier

Published: Jan 11, 2002

References

  • Abdominal surgery-induced inhibition of gastric emptying is mediated in part by interleukin-1 beta
    Coimbra, C.R.; Plourde, V.
  • Development of a radioligand binding assay for 5-HT 4 receptors in guinea-pig and rat brain
    Grossman, C.J.; Kilpatrick, G.J.; Bunce, K.T.
  • Contractile mechanisms of action of gastroprokinetic agents: cisapride, metoclopramide, and domperidone
    Orihata, M.; Sarna, S.K.
  • Investigation on central dopaminergic receptors (D-2) using the antagonistic properties of new benzamides
    Rumigny, J.; Benedetti, M.S.; Dostert, P.
  • Stimulation of gastroduodenal motor activity: dopaminergic and cholinergic modulation
    Schuurkes, J.A.; Helsen, L.F.; Ghoos, E.C.; Eelen, J.G.; Van Neuten, J.M.

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