KDR-5169, a new gastrointestinal prokinetic agent, enhances gastric contractile and emptying activities in dogs and rats.
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-HT4 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-HT4 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.
Tazawa
Shigeki
S
Discovery Research Laboratories, Kissei Pharmaceutical Co. Ltd., 4365-1 Kashiwabara, Hotaka, Minamiazumi, Nagano, 399-8304, Japan. shigeki_tazawa@pharm.kissei.co.jp
Masuda
Naoyuki
N
Koizumi
Takashi
T
Kitazawa
Makio
M
Nakane
Tokio
T
Miyata
Hiroshi
H
D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D065127:Dopamine D2 Receptor Antagonists; D005746:Gastric Emptying / Q000187:drug effects* / Q000502:physiology; D005765:Gastrointestinal Agents / Q000737:chemistry / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D008297:Male; D010528:Peristalsis / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D044422:Receptors, Serotonin, 5-HT4
C451640:4-amino-5-chloro-N-(1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl)-2-(2-hydroxyethoxy)benzamide hydrochloride dihydrate; D001549:Benzamides; D065127:Dopamine D2 Receptor Antagonists; D005765:Gastrointestinal Agents; D010880:Piperidines; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044422:Receptors, Serotonin, 5-HT4