5-HT3 receptor-independent inhibition of the depolarization-induced 86Rb efflux from human neuroblastoma cells, TE671, by ondansetron.

Abstract

The 5-HT3-receptor antagonist, ondansetron, has been shown to have positive effects in selected in-vivo models of memory impairment and anxiety. The exact mechanisms underlying such bioactivities are unknown. In the present work, an 86Rb efflux bioassay was used to show that ondansetron has a unique ability to block voltage-gated potassium channels in TE671 human neuroblastoma cells. This intrinsic potassium-channel-blocking (KCB) property is relatively weak (IC50 20 microM), but is not shared by other 5-HT3-receptor ligands including zatosetron, MDL 72222, LY 278, 584, zacopride, 1-phenylbiguanide, and ICS 205-930 (tropisetron). Pre-incubation of the target neuroblastoma cells with several 5-HT-receptor ligands including 5-hydroxytryptamine, 8-OH-DPAT, ketanserin, 2-methyl-5-HT, as well as a number of potent 5-HT3 agonists and antagonists and two selective neurotoxins, failed to abolish the KCB action of ondansetron. A preliminary structure-activity relationship analysis indicates that the KCB activity of ondansetron is almost entirely attributable to its structural nucleus, 2,3-dihyro-9-methyl-4(1H)-carbazolone. It is hypothesized that the KCB action of ondansetron is mediated through receptors other than 5-HT3 receptors. The KCB activity of ondansetron may be a significant factor in the in-vivo cognition-enhancing activities of this compound, conceivably due to depolarization of the hippocampal synaptic membranes and a consequent augmentation of neurotransmission.

• Authors: J Toral, W Hu, D Critchett, A J Solomon, J E Barrett, P T Sokol, M R Ziai
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 47 Issue 7 Pg. 618-22 (Jul 1995) ISSN: 0022-3573 [Print] England
• PMID: 8568632 (Publication Type: Journal Article)

Chemical References

• Anti-Anxiety Agents
• Benzamides
• Benzofurans
• Biguanides
• Bridged Bicyclo Compounds, Heterocyclic
• Hypoglycemic Agents
• Indazoles
• Indoles
• Neurotoxins
• Potassium Channels
• Receptors, Serotonin
• Receptors, Serotonin, 5-HT3
• Rubidium Radioisotopes
• Serotonin Antagonists
• Serotonin Receptor Agonists
• Tropanes
• LY 278584
• Ondansetron
• Tropisetron
• zatosetron
• zacopride
• bemesetron
• phenyl biguanide

Topics

• Anti-Anxiety Agents (pharmacology)
• Benzamides (pharmacology)
• Benzofurans (pharmacology)
• Biguanides (pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Humans
• Hypoglycemic Agents (pharmacology)
• Indazoles (pharmacology)
• Indoles (pharmacology)
• Neuroblastoma (pathology)
• Neurotoxins (metabolism, pharmacology)
• Ondansetron (pharmacology)
• Potassium Channels (drug effects)
• Receptors, Serotonin (drug effects)
• Receptors, Serotonin, 5-HT3
• Rubidium Radioisotopes (metabolism)
• Serotonin Antagonists (pharmacology)
• Serotonin Receptor Agonists (metabolism, pharmacology)
• Structure-Activity Relationship
• Tropanes (pharmacology)
• Tropisetron
• Tumor Cells, Cultured