A novel selective gamma-aminobutyric acid transport inhibitor demonstrates a functional role for GABA transporter subtype GAT2/BGT-1 in the CNS

Neurochemistry International
Rasmus P ClausenH Steve White

Abstract

The system of GABA transporters in neural cells constitutes an efficient mechanism for terminating inhibitory GABAergic neurotransmission. This transport system is an important therapeutical target in epileptic disorders, but potentially also in other neurological disorders. Thus, selective intervention in GABA uptake has been the subject of extensive research for several decades. In a series of lipophilic diaromatic derivatives of (RS)-3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole (exo-THPO), N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (EF1502) turned out to be an equipotent inhibitor at the mouse transporters GAT1 and GAT2 (BGT-1) but inactive at GAT3 and GAT4. This novel pharmacological profile among GABA uptake inhibitors prompted a thorough investigation of the in vivo properties of this compound. These investigations have for the first time demonstrated a functional role for GABA transporter subtype GAT2/BGT-1, which points to the therapeutic relevance of inhibiting this transporter subtype. An overview of the development and characterisation of EF1502 is presented here.

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Citations

Jan 3, 2007·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Brian S Meldrum, Michael A Rogawski
May 6, 2014·Frontiers in Physiology·Stephen A KempsonNiels C Danbolt
May 16, 2007·The Journal of Biological Chemistry·Bolette ChristiansenHans Braüner-Osborne
Apr 11, 2014·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Masayuki Hiramatsu
Oct 23, 2012·Pharmacological Reports : PR·Kinga SałatKatarzyna Kulig
Aug 21, 2013·Molecular Informatics·Andreas JurikGerhard F Ecker
Mar 25, 2011·Future Medicinal Chemistry·Kinga Sałat, Katarzyna Kulig
May 15, 2012·Pharmacological Reports : PR·Kinga SałatBarbara Malawska
Nov 25, 2018·Toxins·José Luiz LiberatoWagner Ferreira Dos Santos
Feb 15, 2008·Neurochemical Research·Ricardo Augusto de Melo ReisFernando Garcia de Mello
Mar 25, 2011·Future Medicinal Chemistry·Arne SchousboeH Steve White
Feb 13, 2013·Journal of Medicinal Chemistry·Stine B VogensenRasmus P Clausen
Aug 26, 2014·ACS Medicinal Chemistry Letters·Takaaki KobayashiSatoshi Shuto
May 16, 2018·ACS Chemical Neuroscience·Alexandra R SowaMichael R Kilbourn

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