Binding of clozapine to the GABA(B) receptor: clinical and structural insights.

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Nair PC, McKinnon RA, Miners JO, Bastiampillai T

Binding of clozapine to the GABA(B) receptor: clinical and structural insights.

Mol Psychiatry. 2020 Sep;25(9):1910-1919. doi: 10.1038/s41380-020-0709-5. Epub 2020 Mar 13.

PubMed ID

32203158 [ View in PubMed

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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 GABA(B) receptor in the pathogenesis of schizophrenia. It has been hypothesised that clozapine can mediate its actions via the GABA(B) receptor. Baclofen is currently recognised as the prototype GABA(B) 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 GABA(B) receptor along with molecular docking calculations, suggests that clozapine could directly bind to the GABA(B) 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Clozapine	Gamma-aminobutyric acid type B receptor subunit 1	Protein	Humans	Unknown	Positive modulator	Details
Clozapine	Gamma-aminobutyric acid type B receptor subunit 2	Protein	Humans	Unknown	Positive modulator	Details