CHARACTERIZATION OF THE NOVEL 5-HT3 ANTAGONISTS MDL-73147EF (DOLASETRON MESILATE) AND MDL-74156 IN NG108-15 NEUROBLASTOMA X GLIOMA-CELLS

In radioligand binding experiments, MDL 73147EF and MDL 74156 inhibited the binding of [H-3]GR65630 to 5-hydroxytryptamine3 (5-HT3) binding sites on membranes prepared from NG108-15 neuroblastoma x glioma cells. The calculated dissociation constants (K(I)) 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-mu-M) 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.