1. Academic Validation
  2. Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two distinct mechanisms

Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two distinct mechanisms

  • Br J Pharmacol. 2022 Jul;179(14):3675-3692. doi: 10.1111/bph.15807.
Konstantina Bampali 1 Filip Koniuszewski 1 Luca L Silva 1 Sabah Rehman 2 Florian D Vogel 1 Thomas Seidel 3 Petra Scholze 1 Florian Zirpel 1 Arthur Garon 3 Thierry Langer 3 Matthäus Willeit 4 Margot Ernst 1
Affiliations

Affiliations

  • 1 Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University Vienna, Vienna, Austria.
  • 2 Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
  • 3 Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.
  • 4 Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
Abstract

Background and purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABAA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit-containing GABAA receptors. The purpose of this study is to investigate the effects of tricyclic compounds on α5 subunit-containing receptor subtypes.

Experimental approach: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABAA receptor subtypes by two-electrode voltage-clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the α5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings.

Key results: The antipsychotic drugs clozapine and chlorpromazine exerted functional inhibition on multiple GABAA receptor subtypes, including those containing α5-subunits. Based on a chlorpromazine binding site observed in a GABA-gated Bacterial homologue, we identified a novel site in α5 GABAA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands.

Conclusion and implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The chlorpromazine site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABAA receptor subtypes.

Keywords

GABAA receptor; allosteric modulation; antipsychotics; chlorpromazine; clozapine; functional inhibition.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-B1693
    99.98%, Neuroleptic Agent