title: 5-hydroxytryptamine4 receptor agonists facilitate cholinergic transmission in the circular muscle of guinea pig ileum: antagonism by tropisetron and DAU 6285.
abstract: The effect of 5-hydroxytryptamine (5-HT), BIMU 8 (endo-N-(8-methyl-8-azabicyclo [3.2.1.] oct-3-yl)-2,3-dihydro-3-(1-methyl)ethyl-2-oxo-1H-benzimidazole-1- carboxamide hydrochloride) and cisapride was studied on the electrically-induced neurogenic cholinergic twitch contractions in the guinea pig ileum circular muscle. These compounds caused a concentration-dependent increase in the amplitude of submaximal twitch contractions with the following rank order of potency: 5-HT greater than BIMU 8 = cisapride. The effect of 5-HT was competitively antagonized by tropisetron (ICS 205-930) (apparent pA2 value: 6.4), suggesting an interaction at 5-hydroxytryptamine4 (5-HT4) receptors. The novel benzimidazolone derivative DAU 6285 (endo-6-methoxy-8-methyl-8-azabicyclo [3.2.1.] oct-3-yl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylate hydrochloride), antagonized the effect of 5-HT, BIMU 8 and cisapride with apparent pA2 values in the range 7.1-7.3. Our findings demonstrate that cholinergic neurones innervating the circular coat are endowed with excitatory 5-HT4 receptors. DAU 6285 is approximately 5-9-fold more potent than tropisetron as antagonist at these receptors.
authors.affiliation: Department of Internal Medicine and Therapeutics, University of Pavia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Tonini
authors.forename: S M
authors.initials: SM
authors.lastname: Candura
authors.forename: L
authors.initials: L
authors.lastname: Onori
authors.forename: T
authors.initials: T
authors.lastname: Coccini
authors.forename: L
authors.initials: L
authors.lastname: Manzo
authors.forename: C A
authors.initials: CA
authors.lastname: Rizzi
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D020117:Cisapride; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D011950:Receptors, Cholinergic / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D012601:Scopolamine / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology; D000077526:Tropisetron
chemical_list: D001562:Benzimidazoles; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007211:Indoles; D010880:Piperidines; D011950:Receptors, Cholinergic; D011985:Receptors, Serotonin; C074390:DAU 6285; C070189:(endo-N-8-methyl-8-azabicyclo-(3.2.1)oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1-carboxamide; D012701:Serotonin; D013779:Tetrodotoxin; D000077526:Tropisetron; D012601:Scopolamine; D020117:Cisapride