Limiting Activity at β1-Subunit-Containing GABAA Receptor Subtypes Reduces Ataxia

Abstract

GABA A receptor (R) positive allosteric modulators that selectively modulate GABA A Rs containing ␤ 2 -and/or ␤ 3 -over ␤ 1 -subunits have been reported across diverse chemotypes. Examples include loreclezole, mefenamic acid, tracazolate, and etifoxine. In general,"␤ 2/3 -selective" GABA A R positive allosteric modulators are nonbenzodiazepines (nonBZs), do not show ␣-subunit isoform selectivity, yet have anxiolytic efficacy with reduced ataxic/sedative effects in animal models and humans. Here, we report on an enantiomeric pair of nonBZ GABA A R positive allosteric modulators that demonstrate differential ␤-subunit isoform selectivity. We have tested this enantiomeric pair along with a series of other ␤ 2/3 -subunit selective, ␣-subunit isoform-selective, BZ and nonBZ GABA A positive allosteric modulators using electrophysiological, pharmacokinetic, and behavioral assays to test the hypothesis that ataxia may be correlated with the extent of modulation at ␤ 1 -subunit-containing GABA A Rs. Our findings provide an alternative strategy for designing anxioselective allosteric modulators of the GABA A R with BZ-like anxiolytic efficacy by reducing or eliminating activity at ␤ 1 -subunit-containing GABA A Rs.Positive allosteric modulators of the GABA A receptor (R) such as the benzodiazepines (BZs) continue to be used to treat anxiety, despite the well-known side effect of sedation. Diverse drug discovery efforts over two decades have focused on generating "anxioselective" (i.e., reducing anxiety without sedation) GABA A R positive allosteric modulators. Medicinal chemistry efforts have focused primarily on modifications of the BZ template with limited success in reducing sedative liability (Whiting, 2006).One strategy to generate anxioselective positive allosteric modulators involves creation of positive allosteric modulators that selectively modulate individual GABA A R subtypes involved in anxiety, while avoiding those mediating sedation. Several laboratories have focused on ␣-subunit isoform-selective BZ site agonists that evoke positive modulation of ␣ 2 -and ␣ 3 -but not ␣ 1 -subunit-containing GABA A Rs. This "␣ 2/3 -selective" approach is based on pharmacological and genetic data suggesting that ␣ 2 -and ␣ 3 -subunit-containing GABA A Rs mediate the anxiolytic actions of BZs, whereas those with ␣ 1 -subunits, especially the ␣ 1 ␤ 2 ␥ 2 subtype, are thought to mediate their sedative effects (Rudolph et al., 1999;McKernan et al., 2000). Consistent with this general theory, L-838,417 is a ␣ 2,3 -subunit-selective partial agonist BZ receptor ligand reported to be anxioselective in animal models (McKernan et al., 2000). However, recent clinical studies designed to determine whether ␣ 2,3 -subunit selectivity imparts reduced sedative liability has resulted in equivocal results where BZ-like side effects were observed (de Haas et al., 2008(de Haas et al., , 2009. Moreover, the ␣ 3 -subunit-selective BZ site partial agonist adipiplon has potent sedative activity and was in clinical development as a sedative...

Limited central side effects of a β-subunit subtype-selective GABAA receptor allosteric modulator

“…Our studies suggest that the application of the β-subunit subtype selectivity hypothesis may result in compounds that not only have reduced sedation and ethanol potentiation (Gee et al, 2010), but may also have fewer central side effects than those typically associated with classical BZ anxiolytics. However, a major limitation of our study is that the observations are based upon a single chemotype.…”

α4βδ GABA A receptors are high-affinity targets for γ-hydroxybutyric acid (GHB)

“…To date, only few such compounds have been reported (35,36). The preference for β1 may, in part, explain the sleepmediating effects of GHB, because the endogenous pathway of sleep has been shown to depend mainly on β1-containing GABA A receptors, whereas anesthesia and hypnosis are mediated through β3-containing receptors (37,38). β1 is associated with extrasynaptic receptors (39) and abundantly found in the hippocampus and cortex (40), where high-affinity GHB binding sites are predominantly located (6).…”

“…Although less abundant, α4 and δ are also present in hippocampus and cortex (40). β1 (and to a lesser degree, α4 and δ) is present in several brain regions important for modulation of sleep and facilitation of EEG synchronization such as the reticular thalamic nucleus (37), which may underlie the unique therapeutic effect of GHB in narcolepsy. Furthermore, a correlation has been shown between activity at β1-subunit-containing GABA A receptors and ataxia, which is a proposed GHB receptor-mediated effect, because it is induced by GHB receptor-specific ligands and not antagonized by GABA B antagonists (14).…”

Design, Synthesis, and Activity of a Series of Arylpyrid-3-ylmethanones as Type I Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors

“…11 A small library of these compounds were screened for activity as PAMs of human α7 nAChRs expressed in Xenopus oocytes. Compounds were identified with activity at both receptors and modifications to these hits resulted in the identification of novel compounds with selectivity for α7 nAChRs.…”

“…9 In addition to this lack of selectivity, the 1 H NMR spectra of both esters indicate that they are mixtures of Z - and E -isomers. 11 Based on the chemical shift for the aniline NH in the Z -isomers of 1a and b ( Z - 1 ), a hydrogen-bond (H-bond) with the ester carbonyl oxygen atom is implicated (see Figure 2). The major isomer, at least under NMR conditions in CDCl 3 or DMSO-d 6 , is Z -1 , presumably due to the stronger H-bond with the ester in Z -1 compared to the ketone in E-1 .…”