5-HT3 receptor-independent inhibition of the depolarization-induced 86Rb efflux from human neuroblastoma cells, TE671, by ondansetron.
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.
Toral
J
J
CV/CNS Research Section, American Cyanamid Company, Lederle Laboratories, Pearl River, New York 10965, USA.
Hu
W
W
Critchett
D
D
Solomon
A J
AJ
Barrett
J E
JE
Sokol
P T
PT
Ziai
M R
MR
D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D001645:Biguanides / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology; D017294:Ondansetron / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D012414:Rubidium Radioisotopes / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000494:pharmacology; D000077526:Tropisetron; D014407:Tumor Cells, Cultured
D014151:Anti-Anxiety Agents; D001549:Benzamides; D001572:Benzofurans; D001645:Biguanides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007004:Hypoglycemic Agents; D007191:Indazoles; D007211:Indoles; D009498:Neurotoxins; D015221:Potassium Channels; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012414:Rubidium Radioisotopes; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014326:Tropanes; C061531:LY 278584; D017294:Ondansetron; D000077526:Tropisetron; C064877:zatosetron; C055971:zacopride; C042253:bemesetron; C008846:phenyl biguanide