Subtype Selective γ-Aminobutyric Acid Type A Receptor (GABA_AR) Modulators Acting at the Benzodiazepine Binding Site: An Update

Abstract

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter within the central nervous system (CNS) with fast, trans-synaptic and modulatory extrasynaptic effects being mediated by the ionotropic GABA Type A receptors (GABAARs). These receptors are of particular interest since they are the molecular target of a number of pharmacological agents, of which the benzodiazepines (BZDs), such as diazepam, are the best described. The anxiolytic, sedating and myorelaxant effects of BZDs are mediated by separate populations of GABAARs containing either α1, α2, α3 or α5 subunits and the molecular dissection of the pharmacology of BZDs indicates that subtype-selective GABAAR modulators will have novel pharmacological profiles. This is best exemplified by α2/α3-GABAAR positive allosteric modulators (PAMs) and α5-GABAAR negative allosteric modulators (NAMs), which were originally developed as non-sedating anxiolytics and cognition enhancers, respectively. This review aims to summarize the current state of the field of subtype-selective GABAAR modulators acting via the BZD binding site and their potential clinical indications. Recently, high-resolution cryo-electron microscopy (cryo-EM) structures of the human α1β2γ2 and α1β3γ2 GABAARs have been reported. 11,12,19 The analysis of the receptors in complexes with the orthosteric agonist GABA and the GABA binding site antagonist bicuculline as well as the openchannel blocker pycrotoxin and BZD binding site ligands such as diazepam (Figure 1), alprazolam and flumazenil not only provide a detailed insight into the overall assembly and heteromeric interactions of GABAARs, but have also started to reveal the structural basis of receptor activation and allosteric modulation. The focus of the present review will be on compounds that bind to the BZD site with more detailed descriptions regarding the other GABAAR binding sites being available elsewhere. 14,15,20,21

8-Substituted Triazolobenzodiazepines: In Vitro and In Vivo Pharmacology in Relation to Structural Docking at the α1 Subunit-Containing GABAA Receptor

“…Since the introduction of chlordiazepoxide and diazepam in the 1960's, BZ-type drugs have become important psychiatric tools for the management of anxiety and sleep disorders. Over the past two decades, intense interest in exploiting the BZ-sensitive GABA A receptor subtypes has resulted in clinical candidates that lack some of the deleterious side effects associated with this class of drugs (for review, see Maramai et al, 2020). A recent 1.0 0.3 1.0 3.0 1.0 1.0 0.3 *Triazolam data were derived from previously published reports using the same methodology (Platt et al, 2002;Duke et al, 2006;Licata et al, 2009).…”

“…) demonstrated a greater degree of intrinsic efficacy at α2/ α3GABA A subtypes relative to α1GABA A subtypes (e.g., Witkin et al, 2017;Witkin et al, 2020), although at higher concentrations this and related compounds do show at least partial intrinsic efficacy at the latter subtypes (leading to the suggested descriptor of "α2/α3GABA A subtype-preferring compounds"; Maramai et al, 2020).…”

“…This differentiation was most notable for α2GABA A receptors, for which the positive modulation of GABA-mediated Cl − currents was 70% relative to triazolam. This degree of functional selectivity has resulted in "anxioselective" effects for other compounds (for review, see Sieghart and Savić, 2018;Maramai et al, 2020). At higher concentrations, however, functional selectivity was not evident, suggesting that SH-TRI-108 would show behavioral selectivity over a narrower range of doses than a compound deemed functionally selective based on an absence of intrinsic efficacy at α1GABA A receptors.…”

Targeting Endocannabinoid Metabolism: an Arrow with Multiple Tips Against Multiple Sclerosis

“…The orphan G‐protein‐coupled receptor GPR55 (Figures 1 and 2) has been investigated as an “additional” CBR and target for ECs, [79] even if its pharmacology is complicated and there is still the need to completely unveil its exact role within ECS [58,80] . γ‐aminobutyric acid (GABA) receptor A (GABA A R) [81] (Figure 2) is also triggered by ECs and 2‐AG is able to potentiate this receptor at low concentrations of GABA [82] . This effect has attracted attention since the activation of GABA A Rs and manipulation of GABAergic activity positively influence autoimmune inflammatory statuses, as demonstrated in EAE models [83] .…”

Synthesis of 4‐Hydroxy‐2‐pyridinone Derivatives and Evaluation of Their Antioxidant/Anticancer Activities

“…In addition, pyridinone derivatives are the common subunit in diverse biologically active natural products such as pyridinone alkaloids, e. g. flavipucine, funiculosin, ilicicolin H and the antibiotic kirromycin as a representative of the elfamycins [14b] . In the last decade, the quest for more potent cardiotonic agents, [15] and sedative [16] amongst these types of compounds has steadily continued. Furthermore, pyridinone derivatives have been recently used as ligands for the late 3d‐metals [17] .…”