Abstract
The interaction of the psychotropic agent olanzapine with serotonin 5-HT(3) and 5-HT(6) receptors was investigated. Olanzapine did not contract the isolated guinea pig ileum, but blocked contractions induced by the 5-HT(3) receptor agonist 2-methyl serotonin (2-CH(3) 5-HT) with a pK(B) value of 6.38+/-0.03, close to the affinity of the 5-HT(3) receptor antagonist ondansetron. The atypical antipsychotic risperidone (1 microM) did not significantly inhibit 2-CH(3) 5-HT-induced contractions. Olanzapine had high affinity (pK(i)=8.30+/-0.06) for human 5-HT(6) receptors in radioligand binding studies. Olanzapine did not stimulate [35S]guanosine-5'-O-(3-thio)triphosphate ([35S]GTPgammaS) binding to the G protein G(s) in cells containing human 5-HT(6) receptors, but inhibited 5-HT-stimulated [35S]GTPgammaS binding (pK(B)=7.38+/-0.16). Among other antipsychotics investigated, clozapine antagonized 5-HT(6) receptors with a pK(B)=7.42+/-0.15, ziprasidone was three-fold less potent, and risperidone, quetiapine and haloperidol were weak antagonists. Thus, olanzapine was not an agonist, but was a potent antagonist at 5-HT(6) receptors and had marked antagonism at 5-HT(3) receptors.
MeSH terms
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Animals
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Benzodiazepines
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Binding, Competitive / drug effects
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Clozapine / pharmacology
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Dibenzothiazepines / pharmacology
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Dose-Response Relationship, Drug
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Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
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Guinea Pigs
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Haloperidol / pharmacology
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HeLa Cells
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Humans
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Ileum / drug effects
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Ileum / physiology
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In Vitro Techniques
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Indoles / pharmacology
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Lysergic Acid / metabolism
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Muscle Contraction / drug effects
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Olanzapine
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Ondansetron / pharmacology
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Pirenzepine / analogs & derivatives*
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Pirenzepine / pharmacology*
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Quetiapine Fumarate
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Receptors, Serotonin / drug effects*
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Receptors, Serotonin / metabolism
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Receptors, Serotonin, 5-HT3
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Risperidone / pharmacology
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Selective Serotonin Reuptake Inhibitors / pharmacology
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Serotonin / analogs & derivatives*
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Serotonin / pharmacology
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Serotonin Antagonists / pharmacology*
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Serotonin Receptor Agonists / pharmacology
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Sulfur Radioisotopes
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Tritium
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Tropisetron
Substances
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Dibenzothiazepines
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Indoles
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Receptors, Serotonin
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Receptors, Serotonin, 5-HT3
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Serotonin Antagonists
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Serotonin Receptor Agonists
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Serotonin Uptake Inhibitors
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Sulfur Radioisotopes
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serotonin 6 receptor
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Tritium
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Benzodiazepines
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Quetiapine Fumarate
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Serotonin
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Guanosine 5'-O-(3-Thiotriphosphate)
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Pirenzepine
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Ondansetron
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Tropisetron
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2-methyl-5-HT
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Lysergic Acid
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Clozapine
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Haloperidol
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Risperidone
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Olanzapine