title: A novel selective gamma-aminobutyric acid transport inhibitor demonstrates a functional role for GABA transporter subtype GAT2/BGT-1 in the CNS.
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.
authors.affiliation: Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark. rac@dfuni.dk
authors.forename: Rasmus P
authors.initials: RP
authors.lastname: Clausen
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
authors.forename: Orla M
authors.initials: OM
authors.lastname: Larsson
authors.forename: Arne
authors.initials: A
authors.lastname: Schousboe
authors.forename: Povl
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D050485:GABA Plasma Membrane Transport Proteins / Q000502:physiology*; D058805:GABA Uptake Inhibitors; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C510806:EF1502; D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D007555:Isoxazoles