Cited by 205Receptor Mechanisms and SignalingNeurotransmitter Receptor Influence on BehaviorSchizophrenia research and treatment

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Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and α1-adrenergic receptors in vitro

Bymaster, F·1999·Schizophrenia Research

DOI 10.1016/s0920-9964(98)00146-7

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Abstract

The atypical antipsychotic olanzapine has relatively high affinity for a number of neuronal receptors in radioreceptor binding assays. The ability of olanzapine to activate or antagonize a number of neuronal receptors was investigated in vitro, in cell lines transfected selectively with receptor subtypes and in receptor-selective isolated tissue studies. Olanzapine had no agonist activity at any of the receptors examined. However, olanzapine was a potent antagonist of 5-HT-stimulated increases in IP3 in cell lines transfected with 5-HT2A or 5-HT2B receptors with IC50 values of 30-40 nM. Olanzapine weakly blocked 5-HT-induced formation of IP3 in cell lines transfected with 5-HT2c receptors, but in this cell line potently inhibited 5-HT-stimulated [35S]GTP gamma S binding with a Ki value of 15 nM. Olanzapine blocked dopamine-stimulated adenylyl cyclase in rat retina with modest potency (Ki = 69 nM), consistent with its relatively low affinity for dopamine D1 receptors. Olanzapine blocked agonist-induced activities at the muscarinic receptor subtypes M1, M2, M3, and M5 with Ki values of 70, 622, 126, and 82 nM, respectively. In studies using cell lines transfected with muscarinic M4 receptors, olanzapine and the atypical antipsychotic clozapine did not have agonist activities as determined with cAMP inhibition and stimulation assays, arachidonic acid release and [35S]GTP gamma S binding assays. However, olanzapine antagonized agonist-induced effects in muscarinic M4 cells with a Ki value of 350 nM. In isolated tissue studies, olanzapine potently blocked agonist-induced effects at alpha 1-adrenergic and histamine H1 receptors (KB = 9 and 19 nM, respectively). Thus, olanzapine was an antagonist at all receptors investigated and was a particularly potent antagonist at 5-HT2A, 5-HT2B, 5-HT2C, alpha 1-adrenergic and histamine H1 receptors. Olanzapine was a weaker antagonist at muscarinic and dopamine D1 receptors.

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Authors: Bymaster, F.
Affiliations: Eli Lilly (United States) (US)
Corresponding author: Bymaster, F
Venue: Schizophrenia Research
Publisher: Elsevier BV
Published: 1999-05-04
Volume: 37
Issue: 1
Pages: 107-122
ISSN: 0920-9964 (ISSN-L)
DOI: 10.1016/s0920-9964(98)00146-7
OpenAlex: W2113107587
Cited by: 200
References: 62
Citations by year: 2026: 6 · 2025: 6 · 2024: 6 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 5 · 2019: 6 · 2018: 4 · 2017: 5 · 2016: 8 · 2015: 10 · 2014: 5 · 2013: 5 · 2012: 10
FWCI: 3.56
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Schizophrenia Research (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords: olanzapine, atypical antipsychotics
MeSH terms: Olanzapine, Adenylyl Cyclases, Animals, Benzodiazepines, Cells, Cultured, Cricetinae, Kinetics, Pirenzepine, Receptors, Adrenergic, alpha, Receptors, Histamine H1, Receptors, Muscarinic, Receptors, Serotonin, Retina, Receptors, Dopamine D1, Rats

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Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and α1-adrenergic receptors in vitro

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