title: Potent antagonism of 5-HT(3) and 5-HT(6) receptors by olanzapine.
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.
authors.affiliation: Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0501, USA. F.Bymaster@lilly.com
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: J F
authors.initials: JF
authors.lastname: Falcone
authors.forename: D
authors.initials: D
authors.lastname: Bauzon
authors.forename: J S
authors.initials: JS
authors.lastname: Kennedy
authors.forename: K
authors.initials: K
authors.lastname: Schenck
authors.forename: N W
authors.initials: NW
authors.lastname: DeLapp
authors.forename: M L
authors.initials: ML
authors.lastname: Cohen
mesh_terms: D000818:Animals; D001569:Benzodiazepines; D001667:Binding, Competitive / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology; D003987:Dibenzothiazepines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006220:Haloperidol / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008237:Lysergic Acid / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D000077152:Olanzapine; D017294:Ondansetron / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000069348:Quetiapine Fumarate; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3; D018967:Risperidone / Q000494:pharmacology; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013462:Sulfur Radioisotopes; D014316:Tritium; D000077526:Tropisetron
chemical_list: D001569:Benzodiazepines; D003024:Clozapine; D003987:Dibenzothiazepines; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006220:Haloperidol; D007211:Indoles; D008237:Lysergic Acid; D000077152:Olanzapine; D017294:Ondansetron; D010890:Pirenzepine; D000069348:Quetiapine Fumarate; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D018967:Risperidone; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D013462:Sulfur Radioisotopes; D014316:Tritium; D000077526:Tropisetron; C097216:serotonin 6 receptor; C045918:2-methyl-5-HT