The α2β3γ2 GABAA receptor preferring agonist NS11394 aggravates dystonia in the phenotypic dt model

Spröte, C.; Richter, Franziska; Bauer, Anne; Gerstenberger, Julia; Richter, Angelika

doi:10.1016/j.ejphar.2016.09.040

Cited by 2 publications

(3 citation statements)

References 26 publications

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“…84,85,86 In this regard, NS11394 has also been shown to be analgesic in a variety of inflammatory and neuropathic pain models. 87 NS11394 unexpectedly also caused a worsening of symptoms in the dt sz mutant hamster model of dystonia, 88 in contrast to clonazepam which demonstrated a marked beneficial effect and zolpidem which showed a modest improvement. 89 Figure 8.…”

Section: α2/α3-gabaar Pamsmentioning

confidence: 97%

“…There is considerable evidence to suggest that α2/α3-GABA A R PAMs may exert analgesic effects in the spinal cord, probably related to the α2 subtype. − In this regard, NS11394 has also been shown to be analgesic in a variety of inflammatory and neuropathic pain models . NS11394 unexpectedly also caused a worsening of symptoms in the dt sz mutant hamster model of dystonia, in contrast to clonazepam, which demonstrated a marked beneficial effect and zolpidem which showed a modest improvement …”

Section: α2/α3-gabaar Pamsmentioning

confidence: 99%

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

et al. 2019

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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

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Section: α2/α3-gabaar Pamsmentioning

confidence: 97%

Section: α2/α3-gabaar Pamsmentioning

confidence: 99%

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

et al. 2019

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“…Similarly, other GABA-enhancing substances such as benzodiazepines, zonisamide, and sodium oxybate produce similar effects as alcohol. 27,[30][31][32][33][34] In particular, sodium oxybate effectively reduced dystonia in patients with alcohol-responsive laryngeal dystonia. 35 However, antidystonic drugs often have only a partial effect in a minority of patients, 36 which is in keeping with our observation that only 30% of patients showed a response to alcohol.…”

Section: Figure Degree Of Alcohol Responsiveness Across Different Dysmentioning

confidence: 99%

Predictors of alcohol responsiveness in dystonia

et al. 2018

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ObjectiveTo determine predictors of alcohol responsiveness in a large cohort of patients with dystonia.MethodsA total of 2,159 participants with dystonia were prospectively enrolled in the cross-sectional Dystonia Coalition multicenter study. Patients with secondary, combined, or confirmed genetic dystonia (total n = 164) or unknown alcohol responsiveness (n = 737) were excluded. Patients answered a standardized questionnaire and were clinically examined using a standardized video protocol and the Burke-Fahn-Marsden Dystonia Rating Scale. Alcohol responsiveness was determined by patients' self-report.ResultsA total of 1,258 patients with isolated dystonia (mean age: 59.5 ± 12.2 years; 898 women) met the inclusion criteria; 369 patients (29.3%) reported improvement of dystonia after alcohol consumption. Alcohol responsiveness was not related to sex (p = 0.742), age (p = 0.715), or severity of dystonia (p = 0.623). Age at onset was lower in patients who responded to alcohol (p < 0.001). Alcohol responsiveness differed across dystonia subgroups (multifocal/generalized > segmental [p = 0.014]; cervical and laryngeal > cranial and limb [p < 0.001]) and was related to a positive family history of movement disorders (p = 0.001), and presence of tremor (p < 0.001).ConclusionThe association of alcohol responsiveness with a positive family history for movement disorders, generalized dystonia, and an earlier age at onset suggests that patients with dystonia who have an underlying genetic contribution may be more likely to respond beneficially to alcohol. The fact that dystonic tremor may respond to alcohol is in keeping with the observation that the intake of GABAergic drugs may have a beneficial effect in a proportion of patients.

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The α2β3γ2 GABAA receptor preferring agonist NS11394 aggravates dystonia in the phenotypic dt model

Cited by 2 publications

References 26 publications

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

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

Predictors of alcohol responsiveness in dystonia

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The α2β3γ2 GABAA receptor preferring agonist NS11394 aggravates dystonia in the phenotypic dt model

Cited by 2 publications

References 26 publications

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

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

Predictors of alcohol responsiveness in dystonia

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

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