Characterization of a novel 5-HT sub(4) receptor antagonist of the azabicycloalkyl benzimidazolone class: DAU 6285

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 1992-01, Vol.345 (3), p.264-269
• Main Authors: Dumuis, A, Gozlan, H, Sebben, M, Ansanay, H, Rizzi, CA, Turconi, M, Monferini, E, Giraldo, E, Schiantarelli, P
• Format: Article
• Language: English
• ISSN: 0028-1298

Three chemical classes of serotonin 5-HT sub(4) 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-HT sub(4) 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 K sub(i) values of 220, 181 and 255 nmol/l, respectively. In addition, DAU 6285 showed poor activity as a 5-HT sub(3) receptor ligand with respect to tropisetron, as demonstrated by in vitro binding studies (K sub(i), 322 vs 2.8 nmol/l) and by its antagonistic activity in the Bezold-Jarisch reflex test (ID sub(50), 231 vs 0.5 mu g/kg, i.v.). No significant binding (K sub(i) > 10 mu mol/l) of DAU 6285 to serotonergic 5-HT sub(1A), 5-HT sub(1B), 5-HT sub(1C), 5-HT sub(1D), and 5-HT sub(2) receptors as well as to adrenergic alpha sub(1), alpha sub(2), dopaminergic D sub(1), D sub(2) or muscarinic M sub(1)-M sub(3) receptor subtypes was found.