caa a22 4500 469079312 CHVBK 20180323132945.0 cr unu---uuuuu 170328e19920301xx s 000 0 eng 10.1007/BF00168685 doi (NATIONALLICENCE)springer-10.1007/BF00168685 Characterization of a novel 5-HT4 receptor antagonist of the azabicycloalkyl benzimidazolone class: DAU 6285 [Elektronische Daten] [A. Dumuis, H. Gozlan, M. Sebben, H. Ansanay, C. Rizzi, M. Turconi, E. Monferini, E. Giraldo, P. Schiantarelli, H. Ladinsky, J. Bockaert] Summary: 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 μg/kg, i.v.). No significant binding (Ki>10 μmol/l) of DAU 6285 to serotonergic 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT2 receptors as well as to adrenergic α1, α2, 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. Springer-Verlag, 1992 5-HT4 receptor antagonist nationallicence 5-HT3 receptor antagonist nationallicence Azabicycloalkyl benzimidazolone derivatives nationallicence Dumuis A. Centre CNRS-INSERM de Pharmacologie-Endocrinologie, Rue de la Cardonille, F-34094, Montpellier Cedex 5, France aut Gozlan H. Laboratoire de Neurobiologie Cellulaire et Fonctionnelle, INSERM U288, CHU Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, F-75634, Paris Cedex 13, France aut Sebben M. Centre CNRS-INSERM de Pharmacologie-Endocrinologie, Rue de la Cardonille, F-34094, Montpellier Cedex 5, France aut Ansanay H. Centre CNRS-INSERM de Pharmacologie-Endocrinologie, Rue de la Cardonille, F-34094, Montpellier Cedex 5, France aut Rizzi C. Boehringer Ingelheim Italia, Istituto De Angeli S.p.A., I-20139, Milan, Italy aut Turconi M. Boehringer Ingelheim Italia, Istituto De Angeli S.p.A., I-20139, Milan, Italy aut Monferini E. Boehringer Ingelheim Italia, Istituto De Angeli S.p.A., I-20139, Milan, Italy aut Giraldo E. Boehringer Ingelheim Italia, Istituto De Angeli S.p.A., I-20139, Milan, Italy aut Schiantarelli P. Boehringer Ingelheim Italia, Istituto De Angeli S.p.A., I-20139, Milan, Italy aut Ladinsky H. Boehringer Ingelheim Italia, Istituto De Angeli S.p.A., I-20139, Milan, Italy aut Bockaert J. Laboratoire de Neurobiologie Cellulaire et Fonctionnelle, INSERM U288, CHU Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, F-75634, Paris Cedex 13, France aut Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 345/3(1992-03-01), 264-269 0028-1298 345:3<264 1992 345 210 https://doi.org/10.1007/BF00168685 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00168685 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Dumuis A. Centre CNRS-INSERM de Pharmacologie-Endocrinologie, Rue de la Cardonille, F-34094, Montpellier Cedex 5, France aut NATIONALLICENCE 700 1- Gozlan H. Laboratoire de Neurobiologie Cellulaire et Fonctionnelle, INSERM U288, CHU Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, F-75634, Paris Cedex 13, France aut NATIONALLICENCE 700 1- Sebben M. Centre CNRS-INSERM de Pharmacologie-Endocrinologie, Rue de la Cardonille, F-34094, Montpellier Cedex 5, France aut NATIONALLICENCE 700 1- Ansanay H. Centre CNRS-INSERM de Pharmacologie-Endocrinologie, Rue de la Cardonille, F-34094, Montpellier Cedex 5, France aut NATIONALLICENCE 700 1- Rizzi C. Boehringer Ingelheim Italia, Istituto De Angeli S.p.A., I-20139, Milan, Italy aut NATIONALLICENCE 700 1- Turconi M. Boehringer Ingelheim Italia, Istituto De Angeli S.p.A., I-20139, Milan, Italy aut NATIONALLICENCE 700 1- Monferini E. Boehringer Ingelheim Italia, Istituto De Angeli S.p.A., I-20139, Milan, Italy aut NATIONALLICENCE 700 1- Giraldo E. Boehringer Ingelheim Italia, Istituto De Angeli S.p.A., I-20139, Milan, Italy aut NATIONALLICENCE 700 1- Schiantarelli P. Boehringer Ingelheim Italia, Istituto De Angeli S.p.A., I-20139, Milan, Italy aut NATIONALLICENCE 700 1- Ladinsky H. Boehringer Ingelheim Italia, Istituto De Angeli S.p.A., I-20139, Milan, Italy aut NATIONALLICENCE 700 1- Bockaert J. Laboratoire de Neurobiologie Cellulaire et Fonctionnelle, INSERM U288, CHU Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, F-75634, Paris Cedex 13, France aut NATIONALLICENCE 773 0- Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 345/3(1992-03-01), 264-269 0028-1298 345:3<264 1992 345 210 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer