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.
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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)
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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
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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
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