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)

Identification of serotonin 5-HT4 recognition sites in the porcine caudate nucleus by radioligand binding.

Specific binding for the serotonin 5-HT4 receptor (5-HT4R) radioligand [3H]GR 113808 was identified in pig caudate nucleus and characterized by serotonin subtype selective drugs. Binding was inhibited by serotonin and by synthetic indoles, benzamides and benzimidazolones known to characterize the 5-HT4R in functional tests. Rank order of potency of 5-HT4R antagonists was: GR 125487 (Ki, 0.19 nM) > GR 113808 >> SC 53606 > SDZ 205,557 > RS 235971/190 > DAU 6285 > tropisetron > DAU 6215. GR 125487 and GR 113808 were highly selective with respect to the 5-HT3 receptor (5-HT3R). Rank order of potency of 5-HT4R agonists was: SC 53116 (Ki, 21 nM) > BIMU 1 > cisapride > BIMU 8 > serotonin > renzapride > S-zacopride > metoclopramide > R-zacopride > 5-methoxytryptamine >> 5-carboxamidotryptamine. BIMU 8, renzapride, metoclopramide and the zacopride enantiomers gave shallow competition curves. The agonists were substantially less selective than the antagonists with respect to the 5-HT3R. With only two exceptions, SCH 23390 and metergoline, which bound with sub-microM affinity to the 5-HT4R, binding was not inhibited by compounds selective for other G-protein-coupled or channel-gated receptors. Highly significant correlations in affinities of compounds for 5-HT4R in caudata of pigs, guinea pigs and humans were found suggesting no difference among mammalian species.