title: Characterization of a novel 5-HT4 receptor antagonist of the azabicycloalkyl benzimidazolone class: DAU 6285.
abstract: 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.
authors.affiliation: Centre CNRS-INSERM de Pharmacologie-Endocrinologie, Montpellier, France.
authors.forename: A
authors.initials: A
authors.lastname: Dumuis
authors.forename: H
authors.initials: H
authors.lastname: Gozlan
authors.forename: M
authors.initials: M
authors.lastname: Sebben
authors.forename: H
authors.initials: H
authors.lastname: Ansanay
authors.forename: C A
authors.initials: CA
authors.lastname: Rizzi
authors.forename: M
authors.initials: M
authors.lastname: Turconi
authors.forename: E
authors.initials: E
authors.lastname: Monferini
authors.forename: E
authors.initials: E
authors.lastname: Giraldo
authors.forename: P
authors.initials: P
authors.lastname: Schiantarelli
authors.forename: H
authors.initials: H
authors.lastname: Ladinsky
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001921:Brain / Q000166:cytology / Q000648:ultrastructure; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D004622:Embryo, Mammalian; D006339:Heart Rate / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D008636:Mesencephalon / Q000166:cytology / Q000648:ultrastructure; D051379:Mice; D051381:Rats; D011985:Receptors, Serotonin / Q000145:classification / Q000378:metabolism; D012018:Reflex / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013268:Stimulation, Chemical; D000077526:Tropisetron
chemical_list: D001549:Benzamides; D001562:Benzimidazoles; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; 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; D000077526:Tropisetron; C053006:renzapride; D000242:Cyclic AMP