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

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

23 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

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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.",

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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

TY - JOUR

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

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