A novel GABAA alpha 5 receptor inhibitor with therapeutic potential

István Ling; Balázs Mihalik; Lori-An Etherington; Gábor Kapus; Adrienn Pálvölgyi; Gábor Gigler; Szabolcs Kertész; Attila Gaál; Katalin Pallagi; Péter Kiricsi; Éva Szabó; Gábor Szénási; Lilla Papp; László G. Hársing; György Lévay; Michael Spedding; Jeremy J. Lambert; Delia Belelli; József Barkóczy; Balázs Volk; Gyula Simig; István Gacsályi; Ferenc A. Antoni

doi:10.1016/j.ejphar.2015.07.005

A novel GABA_A alpha 5 receptor inhibitor with therapeutic potential

István Ling
, Balázs Mihalik
, Lori-An Etherington
, Gábor Kapus
, Adrienn Pálvölgyi
, Gábor Gigler
, Szabolcs Kertész
, Attila Gaál
, Katalin Pallagi
, Péter Kiricsi
, Éva Szabó
, Gábor Szénási
, Lilla Papp
, László G. Hársing
, György Lévay
, Michael Spedding
, Jeremy J. Lambert
, Delia Belelli
, József Barkóczy
, Balázs Volk

Gyula Simig, István Gacsályi, Ferenc A. Antoni (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

25 Citations (Scopus)

Abstract

Novel 2,3-benzodiazepine and related isoquinoline derivatives, substituted at position 1 with a 2-benzothiophenyl moiety, were synthesized to produce compounds that potently inhibited the action of GABA on heterologously expressed GABA_A receptors containing the alpha 5 subunit (GABA_A α₅), with no apparent affinity for the benzodiazepine site. Substitutions of the benzothiophene moiety at position 4 led to compounds with drug-like properties that were putative inhibitors of extra-synaptic GABA_A α₅ receptors and had substantial blood-brain barrier permeability. Initial characterization in vivo showed that 8-methyl-5-[4-(trifluoromethyl)-1-benzothiophen-2-yl]-1,9-dihydro-2H-[1,3]oxazolo[4,5-h][2,3]benzodiazepin-2-one was devoid of sedative, pro-convulsive or motor side-effects, and enhanced the performance of rats in the object recognition test. In summary, we have discovered a first-in-class GABA-site inhibitor of extra-synaptic GABA_A α₅ receptors that has promising drug-like properties and warrants further development.

Original language	English
Pages (from-to)	497-507
Number of pages	11
Journal	European Journal of Pharmacology
Volume	764
Early online date	11 Jul 2015
DOIs	https://doi.org/10.1016/j.ejphar.2015.07.005
Publication status	Published - 5 Oct 2015

Keywords

2,3-Benzodiazepine
Benzothiophene
Extrasynaptic receptors
GABA
GABAA antagonist
Isoquinoline
Nootropic agents
Object recognition test

ASJC Scopus subject areas

Pharmacology

Access to Document

10.1016/j.ejphar.2015.07.005

Cite this

Ling, I., Mihalik, B., Etherington, L.-A., Kapus, G., Pálvölgyi, A., Gigler, G., Kertész, S., Gaál, A., Pallagi, K., Kiricsi, P., Szabó, É., Szénási, G., Papp, L., Hársing, L. G., Lévay, G., Spedding, M., Lambert, J. J., Belelli, D., Barkóczy, J., ... Antoni, F. A. (2015). A novel GABA_A alpha 5 receptor inhibitor with therapeutic potential. European Journal of Pharmacology, 764, 497-507. https://doi.org/10.1016/j.ejphar.2015.07.005

@article{8648ba1d110d47f59383a94f478a263a,

title = "A novel GABAA alpha 5 receptor inhibitor with therapeutic potential",

abstract = "Novel 2,3-benzodiazepine and related isoquinoline derivatives, substituted at position 1 with a 2-benzothiophenyl moiety, were synthesized to produce compounds that potently inhibited the action of GABA on heterologously expressed GABAA receptors containing the alpha 5 subunit (GABAA α5), with no apparent affinity for the benzodiazepine site. Substitutions of the benzothiophene moiety at position 4 led to compounds with drug-like properties that were putative inhibitors of extra-synaptic GABAA α5 receptors and had substantial blood-brain barrier permeability. Initial characterization in vivo showed that 8-methyl-5-[4-(trifluoromethyl)-1-benzothiophen-2-yl]-1,9-dihydro-2H-[1,3]oxazolo[4,5-h][2,3]benzodiazepin-2-one was devoid of sedative, pro-convulsive or motor side-effects, and enhanced the performance of rats in the object recognition test. In summary, we have discovered a first-in-class GABA-site inhibitor of extra-synaptic GABAA α5 receptors that has promising drug-like properties and warrants further development.",

keywords = "2,3-Benzodiazepine, Benzothiophene, Extrasynaptic receptors, GABA, GABAA antagonist, Isoquinoline, Nootropic agents, Object recognition test",

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Ling, I, Mihalik, B, Etherington, L-A, Kapus, G, Pálvölgyi, A, Gigler, G, Kertész, S, Gaál, A, Pallagi, K, Kiricsi, P, Szabó, É, Szénási, G, Papp, L, Hársing, LG, Lévay, G, Spedding, M, Lambert, JJ, Belelli, D, Barkóczy, J, Volk, B, Simig, G, Gacsályi, I & Antoni, FA 2015, 'A novel GABA_A alpha 5 receptor inhibitor with therapeutic potential', European Journal of Pharmacology, vol. 764, pp. 497-507. https://doi.org/10.1016/j.ejphar.2015.07.005

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T1 - A novel GABAA alpha 5 receptor inhibitor with therapeutic potential

AU - Ling, István

AU - Mihalik, Balázs

AU - Etherington, Lori-An

AU - Kapus, Gábor

AU - Pálvölgyi, Adrienn

AU - Gigler, Gábor

AU - Kertész, Szabolcs

AU - Gaál, Attila

AU - Pallagi, Katalin

AU - Kiricsi, Péter

AU - Szabó, Éva

AU - Szénási, Gábor

AU - Papp, Lilla

AU - Hársing, László G.

AU - Lévay, György

AU - Spedding, Michael

AU - Lambert, Jeremy J.

AU - Belelli, Delia

AU - Barkóczy, József

AU - Volk, Balázs

AU - Simig, Gyula

AU - Gacsályi, István

AU - Antoni, Ferenc A.

PY - 2015/10/5

Y1 - 2015/10/5

N2 - Novel 2,3-benzodiazepine and related isoquinoline derivatives, substituted at position 1 with a 2-benzothiophenyl moiety, were synthesized to produce compounds that potently inhibited the action of GABA on heterologously expressed GABAA receptors containing the alpha 5 subunit (GABAA α5), with no apparent affinity for the benzodiazepine site. Substitutions of the benzothiophene moiety at position 4 led to compounds with drug-like properties that were putative inhibitors of extra-synaptic GABAA α5 receptors and had substantial blood-brain barrier permeability. Initial characterization in vivo showed that 8-methyl-5-[4-(trifluoromethyl)-1-benzothiophen-2-yl]-1,9-dihydro-2H-[1,3]oxazolo[4,5-h][2,3]benzodiazepin-2-one was devoid of sedative, pro-convulsive or motor side-effects, and enhanced the performance of rats in the object recognition test. In summary, we have discovered a first-in-class GABA-site inhibitor of extra-synaptic GABAA α5 receptors that has promising drug-like properties and warrants further development.

AB - Novel 2,3-benzodiazepine and related isoquinoline derivatives, substituted at position 1 with a 2-benzothiophenyl moiety, were synthesized to produce compounds that potently inhibited the action of GABA on heterologously expressed GABAA receptors containing the alpha 5 subunit (GABAA α5), with no apparent affinity for the benzodiazepine site. Substitutions of the benzothiophene moiety at position 4 led to compounds with drug-like properties that were putative inhibitors of extra-synaptic GABAA α5 receptors and had substantial blood-brain barrier permeability. Initial characterization in vivo showed that 8-methyl-5-[4-(trifluoromethyl)-1-benzothiophen-2-yl]-1,9-dihydro-2H-[1,3]oxazolo[4,5-h][2,3]benzodiazepin-2-one was devoid of sedative, pro-convulsive or motor side-effects, and enhanced the performance of rats in the object recognition test. In summary, we have discovered a first-in-class GABA-site inhibitor of extra-synaptic GABAA α5 receptors that has promising drug-like properties and warrants further development.

KW - 2,3-Benzodiazepine

KW - Benzothiophene

KW - Extrasynaptic receptors

KW - GABA

KW - GABAA antagonist

KW - Isoquinoline

KW - Nootropic agents

KW - Object recognition test

UR - https://www.scopus.com/pages/publications/84938398259

U2 - 10.1016/j.ejphar.2015.07.005

DO - 10.1016/j.ejphar.2015.07.005

M3 - Article

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AN - SCOPUS:84938398259

SN - 0014-2999

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EP - 507

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

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