title: Benzimidazolone derivatives act as 5-HT4 receptor ligands in rat oesophagus.
abstract: Three benzimidazolone derivatives have been evaluated in the tunica muscularis mucosae preparation of the rat oesophagus for activity at the 5-HT4 receptor. BIMU 1 (endo-N-(8-methyl-8-azabicyclo-[3.2.1]oct-3-yl)-2,3-dihydro-3-ethyl-2-ox o- 1H-benzimidazole-1-carboxamide HCl) and BIMU 8 (endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-(1-methyl)eth yl- 2-oxo-1H-benzimidazole-1-carboxamide HCl) acted as potent but partial agonists relative to 5-HT whereas DAU 6215 (N-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)2,3-dihydro-2-oxo-1H- benzimidazole-1-carboxamide HCl) behaved as a competitive antagonist with a pA2 of 6.5. The pEC50 values for BIMU 1 and BIMU 8 were 8.0 and 7.9, respectively, compared with 8.2 for 5-HT. Intrinsic activity values were 0.7 and 0.9, respectively. BIMU 1 and BIMU 8 are the most potent synthetic agonists so far tested in rat oesophagus, and DAU 6215 exhibits an equivalent affinity to ICS 205 930 at the 5-HT4 receptor.
authors.affiliation: Institute of Pharmacology, Syntex Research, Palo Alto, CA 94304.
authors.forename: G S
authors.initials: GS
authors.lastname: Baxter
authors.forename: D E
authors.initials: DE
authors.lastname: Clarke
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004947:Esophagus / Q000187:drug effects; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D009130:Muscle, Smooth / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists
chemical_list: D001562:Benzimidazoles; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C070191:itasetron; C070187:(endo-N-8-methyl-8-azabicyclo(3.2.1)oct-3-yl)-2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazol-1-carboxamide; C070189:(endo-N-8-methyl-8-azabicyclo-(3.2.1)oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1-carboxamide