title: Characterization of the novel 5-HT3 antagonists MDL 73147EF (dolasetron mesilate) and MDL 74156 in NG108-15 neuroblastoma x glioma cells.
abstract: In radioligand binding experiments, MDL 73147EF and MDL 74156 inhibited the binding of [3H]GR65630 to 5-hydroxy-tryptamine3 (5-HT3) binding sites on membranes prepared from NG108-15 neuroblastoma x glioma cells. The calculated dissociation constants (KI) were 20.03 +/- 6.58 and 0.44 +/- 0.18 nM, respectively (means +/- S.E.M., n = 6 and 9, respectively). Application of 5-HT (10-50 microM) to voltage-clamped NG108-15 cells elicited a rapidly desensitizing inward membrane current, characteristic for the activation of 5-HT3 receptors. The 5-HT-induced membrane current was suppressed in a reversible, concentration-dependent manner by MDL 73147EF and MDL 74156EF. The concentrations required to block half the 5-HT response (IC50) were 3.8 and 0.1 nM, respectively. It is concluded that both compounds are potent and reversible antagonists at 5-HT3 receptors in this neuroblastoma cell line.
authors.affiliation: Marion Merrell Dow Research Institute, Strasbourg, France.
authors.forename: P H
authors.initials: PH
authors.lastname: Boeijinga
authors.forename: M
authors.initials: M
authors.lastname: Galvan
authors.forename: B M
authors.initials: BM
authors.lastname: Baron
authors.forename: M W
authors.initials: MW
authors.lastname: Dudley
authors.forename: B W
authors.initials: BW
authors.lastname: Siegel
authors.forename: A L
authors.initials: AL
authors.lastname: Slone
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D005910:Glioma / Q000473:pathology; D006822:Hybrid Cells; D007093:Imidazoles / Q000378:metabolism; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology; D011807:Quinolizines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D007211:Indoles; D011807:Quinolizines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C059068:GR 65630; C060344:dolasetron; C110718:hydrodolasetron