Gastroprokinetic properties of the benzimidazolone derivative BIMU 1, an agonist at 5-hydroxytryptamine4 and antagonist at 5-hydroxytryptamine3 receptors.
We have investigated the in vivo motor stimulating and gastroprokinetic properties of the azabicycloalkyl benzimidazolone derivative BIMU 1 (3-ethyl-2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-oxo-1H- benzimidazole-1-carboxamide hydrochloride) and its binding profile at 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptors, in an attempt to assess the serotonergic mechanism underlying its prokinetic action. BIMU 1 dose-dependently (0.01-0.3 mg/kg i.v.) increased the motility of a denervated pouch of canine stomach. This excitatory action was sensitive to muscarinic blockade. A similar stimulatory effect was exerted by the benzamidic prokinetic agent cisapride (0.03-0.3 mg/kg i.v.) but not by the 5-HT3 receptor antagonist ondansetron (up to 1 mg/kg i.v.). The significance for propulsive efficacy of the motor stimulating activity of BIMU 1 was evaluated in a model of gastric emptying of liquids in the conscious dog. The emptying rate of a non-caloric liquid meal instilled through a gastric fistula was accelerated by both BIMU 1 (0.01-1 mg/kg i.v. and 0.1-3 mg/kg p.o.) and cisapride (0.03-1 mg/kg i.v. and 0.3-10 mg/kg p.o.). Ondansetron (1 mg/kg i.v.) did not show any effect. The activity of the 5-HT4 receptor antagonist DAU 6285 was evaluated in the gastric emptying model per se and in interaction experiments on the accelerating action of BIMU 1 (0.3 mg/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)
Rizzi
C A
CA
Research and Development Division, Boehringer Ingelheim Italia, Milan.
Sagrada
A
A
Schiavone
A
A
Schiantarelli
P
P
Cesana
R
R
Schiavi
G B
GB
Ladinsky
H
H
Donetti
A
A
D000818:Animals; D000897:Anti-Ulcer Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D020117:Cisapride; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009121:Muscle Denervation; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D017294:Ondansetron / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D013270:Stomach / Q000187:drug effects*; D013552:Swine; D014407:Tumor Cells, Cultured
D000897:Anti-Ulcer Agents; D001562:Benzimidazoles; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010880:Piperidines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C070187:(endo-N-8-methyl-8-azabicyclo(3.2.1)oct-3-yl)-2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazol-1-carboxamide; D017294:Ondansetron; D020117:Cisapride