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Binding of clozapine to the GABAB receptor: clinical and structural insights

Molecular Psychiatry volume 25, pages 1910–1919 (2020)Cite this article

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Abstract

Clozapine is the gold-standard agent for treatment resistant schizophrenia but its mechanism of action remains unclear. There is emerging evidence of the potential role of the GABAB receptor in the pathogenesis of schizophrenia. It has been hypothesised that clozapine can mediate its actions via the GABAB receptor. Baclofen is currently recognised as the prototype GABAB receptor agonist. There are some potential clinical similarities between clozapine and baclofen. Indeed, baclofen has been previously proposed for use as an antipsychotic agent. Our analysis of the X-ray crystal structure of GABAB receptor along with molecular docking calculations, suggests that clozapine could directly bind to the GABAB receptor similar to that of baclofen. This finding could lead to a better understanding of the pharmacological uniqueness of clozapine, potential development of a biomarker for treatment resistant schizophrenia and the development of more targeted treatments leading to personalisation of treatment.

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Fig. 1: X-ray crystal structure of the extracellular domain of the GABAB receptor and the chemical structures of GABAB receptor agonists and clozapine.
Fig. 2: Binding mode of clozapine within the extracellular domain of the GABAB receptor and its structural overlay with baclofen.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia

    Pramod C. Nair & John O. Miners

  2. Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia

    Pramod C. Nair, Ross A. McKinnon & John O. Miners

  3. Department of Psychiatry, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia

    Tarun Bastiampillai

  4. South Australian Health and Medical Research Institute, Adelaide, SA, Australia

    Tarun Bastiampillai

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Nair, P.C., McKinnon, R.A., Miners, J.O. et al. Binding of clozapine to the GABAB receptor: clinical and structural insights. Mol Psychiatry 25, 1910–1919 (2020). https://doi.org/10.1038/s41380-020-0709-5

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