Abstract
We have investigated the in vivo motor stimulating and gastroprokinetic properties of the azabicycloalkyl benzimidazolone derivative BIMU 1 (3-ethyl-2,3dihydro-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 iv.) 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/kgiv.and0.3–10 mg/kgp.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 L v.). At 1 mg/kg iv., DAU 6285 was ineffective on its own and failed to antagonize BIMU 1-induced prokinetic action;at the dose of 3 mg/kg i.v., it depressed the gastric emptying rate per se by 15% and totally abolished the accelerating effect of BIMU 1.
In the binding assay, BIMU 1 exhibited an appreciable affinity for 5-HT3 receptors in NG 108-15 cells (KD: 0.8 nmol/l) and for 5-HT4 receptors in pig striatum (KD: 26.5 nmol/l). Compared to BIMU 1, cisapride bound with a similar affinity to 5-HT4 (KD: 35.2 mnol/l) and a much lower affinity to 5-HT3 receptors (KD: 155 nmol/l). By contrast, ondansetron was highly selective for 5-HT3 sites (KD: 4.7 nmol/l), being ineffective in the assay for 5-HT4 receptors (KD > 10000).
Our results show that BIMU 1, like cisapride and unlike ondansetron, is an effective stimulant of gastric motility and propulsion. The action of BIMU 1 appears to depend on 5-HT4 receptor stimulation and to involve the activation of cholinergic nerve pathways.
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Rizzi, C.A., Sagrada, A., Schiavone, A. et al. Gastroprokinetic properties of the benzimidazolone derivative BIMU 1, an agonist at 5-hydroxytryptamine4 and antagonist at 5-hydroxytryptamine3 receptors. Naunyn-Schmiedeberg’s Arch Pharmacol 349, 338–345 (1994). https://doi.org/10.1007/BF00170878
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DOI: https://doi.org/10.1007/BF00170878