GASTROPROKINETIC PROPERTIES OF THE BENZIMIDAZOLONE DERIVATIVE BIMU-1,AN AGONIST AT 5-HYDROXYTRYPTAMINE(4) AND ANTAGONIST AT 5-HYDROXYTRYPTAMINE(3) RECEPTORS

We have investigated the in vivo motor stimulating and gastroprokineti c properties of the azabicycloalkyl benzimidazolone derivative BIMU 1 (3-ethyl-2,3-dihydro 2.1]oct-3-yl)-2-oxo-1H-benzimidazole-1-carboxamid e hydrochloride) and its binding profile at 5-hydroxytryptamine(3) and 5-hydroxytryptamine(4) receptors, in an attempt to assess the seroton ergic mechanism underlying its prokinetic action. BIMU 1 dose-dependen tly (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 w as evaluated in a model of gastric emptying of liquids in the consciou s dog. The emptying rate of a non-caloric liquid meal instilled throug h 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 0.3-10mg/kg p.o.). Ondansetron (1 mg/kg i.v.) did not show any effect. The activi ty of the 5-HT4 receptor antagonist DAU 6285 was evaluated in the gast ric emptying model per se and in interaction experiments on the accele rating action of BIMU 1 (0.3 mg/kg i.v.). At 1 mg/kg i.v., DAU 6285 wa s ineffective on its own and failed to antagonize BIMU 1-induced proki netic action; at the dose of 3 mg/kg i.v., it depressed the gastric em ptying rate per se by 15% and totally abolished the accelerating effec t of BIMU 1. In the binding assay, BIMU 1 exhibited an appreciable aff inity for 5-HT3 receptors in NG 108-15 cells (K-D: 0.8 nmol/l) and for 5-HT4 receptors in pig striatum (K-D: 26.5 nmol/l). Compared to BIMU 1, cisapride bound with a similar affinity to 5-HT4 (K-D: 35.2 nmol/l) and a much lower affinity to 5-HT3 receptors (K-D: 155 nmol/l). By co ntrast, ondansetron was highly selective for 5-HT3 sites (K-D: 4.7 nmo l/l), being ineffective in the assay for 5-HT4 receptors (K-D > 10000) . Our results show that BIMU 1, like cisapride and unlike ondansetron, is an effective stimulant of gastric motility and propulsion. The act ion of BIMU 1 appears to depend on 5-HT4 receptor stimulation and to i nvolve the activation of cholinergic nerve pathways.