AS-5370 potently antagonizes 5-HT3 receptor-mediated responses on NG108-15 cells and on the rat vagus.

The action of a novel 5-HT3 receptor antagonist, AS-5370, has been studied on two electrophysiological models for 5-HT3 receptors: whole-cell patch-clamp recordings from mouse neuroblastoma-rat glioma (NG108-15) cells and grease-gap recordings from rat isolated vagus nerve. The 5-hydroxytryptamine (5-HT)-induced fast inward current of voltage-clamped NG108-15 cells was antagonized by 1 nM AS-5370 in an insurmountable manner. On the rat vagus, AS-5370 reduced the maximum depolarizing response to 5-HT in a concentration-dependent manner. The IC50 for AS-5370 on the rat vagus was 0.3-1.0 nM. The EC50 for 5-HT on the rat vagus was not appreciably affected by AS-5370. On the rat vagus, the (R) enantiomer of AS-5370 was about 30 times more potent than the (S) enantiomer. The antagonist action of AS-5370 on these two cell types was compared with that of (+)-tubocurarine. Unlike tubocurarine, the effect of AS-5370 on NG108-15 cells was not readily reversed during wash. On the rat vagus, tubocurarine antagonized in a competitive manner with an IC50 of 0.3-1.0 microM (pKb = 7.2). It is concluded that AS-5370 is a potent 5-HT3 receptor antagonist on both NG108-15 cells and the rat vagus, but it does not act in a competitive manner.