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5-HT3 receptor-independent inhibition of the depolarization-induced 86Rb efflux from human neuroblastoma cells,
1CV/CNS Research Section, American Cyanamid Company, Lederle Laboratories, Pearl River, New York 10965, USA.
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.
Insights
Ondansetron, a 5-HT3 receptor antagonist, uniquely blocks potassium channels, a property not shared by other related drugs. This potassium-channel-blocking action may explain its cognitive-enhancing effects in vivo.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Ondansetron, a 5-HT3 receptor antagonist, shows promise in memory and anxiety models.
- The precise mechanisms behind ondansetron's bioactivities remain unclear.
Purpose of the Study:
- To investigate the underlying mechanisms of ondansetron's effects.
- To determine if ondansetron interacts with potassium channels.
Main Methods:
- Utilized an 86Rb efflux bioassay in TE671 human neuroblastoma cells.
- Tested other 5-HT3 receptor ligands and neurotoxins for similar activity.
- Performed preliminary structure-activity relationship analysis.
Main Results:
- Ondansetron demonstrated a weak but unique ability to block voltage-gated potassium channels (IC50 20 microM).
- This potassium-channel-blocking (KCB) property was not observed with other tested 5-HT3 ligands.
- The KCB activity was primarily attributed to ondansetron's core structure, 2,3-dihydro-9-methyl-4(1H)-carbazolone.
Conclusions:
- Ondansetron possesses a distinct potassium-channel-blocking activity independent of 5-HT3 receptors.
- This KCB property may contribute to ondansetron's cognition-enhancing effects by modulating hippocampal neurotransmission.