Characterization of antigastrin activity in vivo of CR 2194, a new R-4-benzamido-5-oxo-pentanoic acid derivative.
The antigastrinic activity, in vivo, of CR 2194 (R-4-(3-chlorobenzamido)-5-(8-azaspiro[4.5]decan-8-yl) -5-oxo pentanoic acid) was assessed in various animal species. CR 2194 antagonized pentagastrin-stimulated gastric acid secretion in the rat (ID50 = 11 mg/kg i.v.), dog (ID50 = 5.9 mk/kg i.v. or 28.8 mg/kg os) and cat (ID50 = 15.5 mg/kg i.v.). CR 2194, in the cat, inhibited both competitively and non-competitively the gastric acid secretion stimulated with increased doses of pentagastrin, with a pA2 of 4.89. In the rat and in the dog the antagonism seemed to be non-competitive and the respective pD'2 calculated were 4.54 and 4.42. The interaction of CR 2194 with the gastrin receptors appeared reversible, as demonstrated by the return to normal values of the acid output after the conclusion of the i.v. infusion, during pentagastrin continuous stimulation in the dog. The antigastrin activity was specific: CR 2194 was unable to antagonize the gastric acid secretion stimulated by carbachol or histamine in the rat up to the dose of 100 mg/kg. CR 2194 was effective to antagonize the gastric acid secretion stimulated by gastrin release after meal ingestion in the Heidenhain pouch dog model. The ID50 calculated was 2.89 mg/kg after oral administration. All these characteristics make CR 2194 an important compound in the investigation of the biological effects of gastrin and a potential agent for diagnostic or therapeutic use.
Revel
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Rotta Research Laboratorium, Monza, Milano, Italy.
Ferrari
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F
Makovec
F
F
Rovati
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LC
Impicciatore
M
M
D000818:Animals; D001667:Binding, Competitive; D002415:Cats; D004285:Dogs; D004435:Eating / Q000187:drug effects; D005744:Gastric Acid / Q000378:metabolism; D005747:Gastric Fistula; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D005755:Gastrins / Q000037:antagonists & inhibitors*; D007651:Keto Acids / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D010418:Pentagastrin / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use
D005755:Gastrins; D007651:Keto Acids; D013141:Spiro Compounds; D010418:Pentagastrin; C076954:spiroglumide