ArticlePloS one2009
Identification of a domain which affects kinetics and antagonistic potency of clozapine at 5-HT3 receptors.
Article in PloS one, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
4 citing papers in PubMed, 12 citations in OpenAlex.
- Unveiling the molecular mechanisms of clozapine-induced seizures: a network pharmacology and molecular docking-based investigation.Schizophrenia (Heidelberg, Germany) · 2026Article
- Encoding of both analog- and digital-like behavioral outputs by one C. elegans interneuron.Cell · 2014Article
- Outcome definitions and clinical predictors influence pharmacogenetic associations between HTR3A gene polymorphisms and response to clozapine in patients with schizophrenia.Psychopharmacology · 2012Article
- Allosteric modulation of the 5-HT(3) receptor.Current opinion in pharmacology · 2011Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The widely used atypical antipsychotic clozapine is a potent competitive antagonist at 5-HT(3) receptors which may contribute to its unique psychopharmacological profile. Clozapine binds to 5-HT(3) receptors of various species. However, the structural requirements of the respective binding site for clozapine remain to be determined. Differences in the primary sequences within the 5-HT(3A) receptor gene in schizophrenic patients may result in an alteration of the antipsychotic potency and/or the side effect profile of clozapine. To determine these structural requirements we constructed chimeras with different 5-HT(3A) receptor sequences of murine and human origin and expressed these mutants in human embryonic kidney (HEK) 293 cells. Clozapine antagonises recombinant mouse 5-HT(3A) receptors with higher potency compared to recombinant human 5-HT(3A) receptors. 5-HT activation curves and clozapine inhibition curves yielded the parameters EC(50) and IC(50) for all receptors tested in the range of 0.6 - 2.7 microM and 1.5 - 83.3 nM, respectively. The use of the Cheng-Prusoff equation to calculate the dissociation constant K(b) values for clozapine revealed that an extracellular sequence (length 86 aa) close to the transmembrane domain M1 strongly determines the binding affinity of clozapine. K(b) values of clozapine were significantly lower (0.3-1.1 nM) for receptors containing the murine sequence and higher when compared with receptors containing the respective human sequence (5.8-13.4 nM). Thus, individual differences in the primary sequence of 5-HT(3) receptors may be crucial for the antipsychotic potency and/or the side effect profile of clozapine.
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