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Interaction of clozapine and its nitrenium ion with rat D2 dopamine receptors: in vitro binding and computational study

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Abstract

The interaction of diazepine analogues like clozapine or olanzapine with D2 receptor was greatly affected by a mixture of HRP/H2O2 known to induce the formation of nitrenium ion. Unlike diazepine derivatives, the oxidative mixture had low impact on the affinity of oxa- and thiazepine derivatives such as loxapine, clothiapine or JL13 for the D2 receptor. Molecular docking simulations revealed a huge difference between the mode of interaction of clozapine nitrenium ion and the parent drug. Electronic and geometric changes of the tricyclic ring system caused by the oxidation appeared to prevent the compound finding the correct binding mode and could therefore explain the difference observed in binding affinities.

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Abbreviations

GPCR:

G protein-coupled receptor

ICL:

Intracellular loop

ECL:

Extracellular loop

MD:

Molecular dynamics

HRP:

Horseradish peroxidase

EDTA:

Ethylene diamine tetraacetic acid

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Acknowledgments

The Fonds de la Recherche Scientifique-FNRS (F.R.S.-FNRS) is gratefully acknowledged for financial support. J.-F.L. is Research Director of the F.R.S.-FNRS. S.D. is financially supported by a collective grant from the University of Liège. We wish to thank Christelle Gillissen and Renaud Beckers for technical assistance.

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Authors and Affiliations

  1. Laboratory of Medicinal Chemistry and C.I.R.M. (B36), University of Liège, 4000, Liège, Belgium

    Sébastien Dilly & Jean-François Liégeois

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  1. Sébastien Dilly
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  2. Jean-François Liégeois
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Correspondence to Jean-François Liégeois.

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Dilly, S., Liégeois, JF. Interaction of clozapine and its nitrenium ion with rat D2 dopamine receptors: in vitro binding and computational study. J Comput Aided Mol Des 25, 163–169 (2011). https://doi.org/10.1007/s10822-010-9407-8

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  • DOI: https://doi.org/10.1007/s10822-010-9407-8

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