Identification of a Domain which Affects Kinetics and Antagonistic Potency of Clozapine at 5-HT3 ReceptorsReportar como inadecuado




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The widely used atypical antipsychotic clozapine is a potent competitive antagonist at 5-HT3 receptors which may contribute to its unique psychopharmacological profile. Clozapine binds to 5-HT3 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-HT3A 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-HT3A receptor sequences of murine and human origin and expressed these mutants in human embryonic kidney HEK 293 cells. Clozapine antagonises recombinant mouse 5-HT3A receptors with higher potency compared to recombinant human 5-HT3A receptors. 5-HT activation curves and clozapine inhibition curves yielded the parameters EC50 and IC50 for all receptors tested in the range of 0.6–2.7 µM and 1.5–83.3 nM, respectively. The use of the Cheng-Prusoff equation to calculate the dissociation constant Kb values for clozapine revealed that an extracellular sequence length 86 aa close to the transmembrane domain M1 strongly determines the binding affinity of clozapine. Kb 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-HT3 receptors may be crucial for the antipsychotic potency and-or the side effect profile of clozapine.



Autor: Gerhard Rammes , Christine Hosp, Brigitte Eisensamer, Sascha Tanasic, Caroline Nothdurfter, Walter Zieglgänsberger, Rainer Ruppr

Fuente: http://plos.srce.hr/



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