Tricyclic antipsychotics and antidepressants can inhibit α5‐containing GABA_A receptors by two distinct mechanisms

Abstract

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABA A 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 subunitcontaining GABA A 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 GABA A 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.

Apo2ph4: A Versatile Workflow for the Generation of Receptor-based Pharmacophore Models for Virtual Screening

“…Clozapine is an atypical antipsychotic primarily acting antagonistic on 5HT 2A and dopamine receptors , and is prone to induce seizures . This is attributed to Clozapine also binding to the GABA A R in an antagonistic fashion. , Neurotoxicity, which is often caused by off-target effects, has become a huge concern for the development of new drugs . Hence, there is a big desire in being able to predict toxicity caused by off-target effects in silico.…”

GABAA receptor-mediated seizure liabilities: a mixed-methods screening approach

“…Thus, there remains an unmet need to establish a full inventory of confirmed binding sites in a comprehensive panel of receptor subtypes-a big task to be tackled by future research. Related proteins and homology modeling potentially bridge the gap for binding sites of high scientific interest (Bampali et al 2022;Koniuszewski et al 2022).…”

“…Nevertheless, the amoxapine drug package inserts and pharmacovigilance data indicated potential seizure risk though no indication of the mechanism of action or target. Moreover, the reduction of GABA-elicited currents as an off-target effect has been described previously for different related compounds, such as clozapine (Bampali et al 2022). Based on the unique hit profile and our previous findings on the similar compound clozapine (Bampali et al 2022), amoxapine was selected for a comprehensive experimental follow-up.…”

“…Sites which are localized in or on a single subunit include the so-called lipid-associated sites used by inhibitory steroids in the TMD (9). The binding site used by the tricyclic molecule chlorpromazine in a bacterial homolog's ECD has been recently mapped to the α5 subunit of GABA A Rs (Bampali et al 2022). Additional sites for endogenous molecules have been described and add to the overall complexity of allosteria (Supplementary Figures S1, S2).…”

“…3A). We recently found that clozapine and loxapine, as well as other structurally similar molecules, can inhibit α5β3γ2 receptors as orthosteric antagonists (Bampali et al 2022). Some of these inhibit currents also of α1β3γ2 receptors.…”