Selective inhibition of extra-synaptic α5-GABAA receptors by S44819, a new therapeutic agent

NEUROPHARMACOLOGY

卷:125

Article

Etherington, Lori-An¹  Mihalik, Balazs²  Palvolgyi, Adrienn³  Ling, Istvan³  Pallagi, Katalin³  Kertesz, Szabolcs³  Varga, Peter³  Gunn, Ben G.^1,5  Brown, Adam R.¹  Livesey, Matthew R.^1,6  Monteiro, Olivia¹  Belelli, Delia¹  Barkoczy, Jozsef³  Spedding, Michael⁴  Gacsalyi, Istvan³  Antoni, Ferenc A.^3,6  Lambert, Jeremy J.^1,6 

[1] Dundee Univ, Ninewells Hosp & Med Sch, Med Res Inst, Div Neurosci, Dundee DD1 9SY, Scotland

[2] Biotalentum Kft, Aulich Lajos U 26, H-2100 Godollo, Hungary

[3] Egis Pharmaceut PLC, Pf 100, H-1106 Budapest, Hungary

[4] Inst Recherches Servier, F-78290 Croissy Sur Seine, France

[5] Univ Irvine, Dept Pediat, Irvine, CA USA

[6] Edinburgh Univ Scotland, Ctr Integrat Physiol, Deanery Biomed Sci, Edinburgh EH8 9XD, Midlothian, Scotland

关键词: Tonic inhibition;    Phasic inhibition;    alpha 5-GABA(A) receptors;    Extrasynaptic GABA(A) receptors;    Long term potentiation;    Cognition;   

DOI  :  10.1016/j.neuropharm.2017.08.012

来源: Elsevier

【 摘 要 】

In the mammalian central nervous system (CNS) GABAA receptors (GABAARs) mediate neuronal inhibition and are important therapeutic targets. GABAARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20-30 GABA(A)R subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties. We report the discovery of S44819, a novel tricyclic oxazolo-2,3-benzodiazepine-derivative, that selectively inhibits alpha 5-subunit-containing GABA(A)Rs (alpha 5-GABA(A)Rs). Current alpha 5-GABA(A)R inhibitors bind to the benzodiazepine site. However, in HEK293 cells expressing recombinant alpha 5-GABAARs, S44819 had no effect on H-3-flumazenil binding, but displaced the GABAAR agonist H-3-muscimol and competitively inhibited the GABA-induced responses. Importantly, we reveal that the alpha 5-subunit selectivity is uniquely governed by amino acid residues within the a-subunit F-loop, a region associated with GABA binding. In mouse hippocampal CA1 neurons, S44819 enhanced long-term potentiation (LTP), blocked a tonic current mediated by extrasynaptic alpha 5-GABA(A)Rs, but had no effect on synaptic GABA(A)Rs. In mouse thalamic neurons, S44819 had no effect on the tonic current mediated by S-GABAARs, or on synaptic (alpha 1 beta 2 gamma 2) GABAARs. In rats, S44819 enhanced object recognition memory and reversed scopolamine-induced impairment of working memory in the eight-arm radial maze. In conclusion, S44819 is a first in class compound that uniquely acts as a potent, competitive, selective antagonist of recombinant and native a5-GABAARs. Consequently, S44819 enhances hippocampal synaptic plasticity and exhibits pro-cognitive efficacy. Given this profile, S44819 may improve cognitive function in neurodegenerative disorders and facilitate post-stroke recovery. (C) 2017 Elsevier Ltd. All rights reserved.

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