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 VolkGyula Simig, István Gacsályi, Ferenc A. Antoni

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    15 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 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.

    Original languageEnglish
    Pages (from-to)497-507
    Number of pages11
    JournalEuropean Journal of Pharmacology
    Volume764
    Early online date11 Jul 2015
    DOIs
    Publication statusPublished - 5 Oct 2015

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    Keywords

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

    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 GABAA alpha 5 receptor inhibitor with therapeutic potential. European Journal of Pharmacology, 764, 497-507. https://doi.org/10.1016/j.ejphar.2015.07.005