Characterization of a novel 5-HT4 receptor antagonist of the azabicycloalkyl benzimidazolone class: DAU 6285

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 345; no. 3; p. 264
• Main Authors: Dumuis, A, Gozlan, H, Sebben, M, Ansanay, H, Rizzi, C A, Turconi, M, Monferini, E, Giraldo, E, Schiantarelli, P, Ladinsky, H
• Format: Journal Article
• Language: English
• Published: Germany 01.03.1992
• Subjects: Animals; Benzamides - pharmacology; Benzimidazoles - pharmacology; Brain - cytology; Brain - ultrastructure; Bridged Bicyclo Compounds - pharmacology; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Cyclic AMP - biosynthesis; Embryo, Mammalian; Heart Rate - drug effects; Indoles - pharmacology; Kinetics; Mesencephalon - cytology; Mesencephalon - ultrastructure; Mice; Rats; Receptors, Serotonin - classification; Receptors, Serotonin - metabolism; Reflex - drug effects; Serotonin - pharmacology; Serotonin Antagonists - pharmacology; Stimulation, Chemical; Tropisetron
• ISSN: 0028-1298
• DOI: 10.1007/BF00168685

Three chemical classes of serotonin 5-HT4 receptor agonists have been identified so far: 5-substituted indoles (e.g. 5-HT), benzamides (e.g. renzapride) and benzimidazolones (e.g. BIMU 8). In a search for 5-HT4 receptor antagonists, we have discovered that the benzimidazolone derivative DAU 6285 (for structure see text), is 3-5 times more potent than tropisetron in blocking 5-HT, renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons. Schild plot analysis yielded Ki values of 220, 181 and 255 nmol/l, respectively. In addition, DAU 6285 showed poor activity as a 5-HT3 receptor ligand with respect to tropisetron, as demonstrated by in vitro binding studies (Ki, 322 vs 2.8 nmol/l) and by its antagonistic activity in the Bezold-Jarisch reflex test (ID50, 231 vs 0.5 micrograms/kg, i.v.). No significant binding (Ki greater than 10 mumol/l) of DAU 6285 to serotonergic 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT2 receptors as well as to adrenergic alpha 1, alpha 2, dopaminergic D1, D2 or muscarinic M1-M3 receptor subtypes was found. The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for 5-HT4 receptors, a property confirmed in functional tests, and much lower affinity than tropisetron for 5-HT3 receptors. The compound represents a new interesting tool for investigating the pharmacological and physiological properties of 5-HT4 receptors.