The GABA transporter and its inhibitors.
GABA is the major inhibitory neurotransmitter in the brain and GABA re- uptake from the synaptic cleft is one important mechanism in the regulation of GABA activity. Inhibition of the re-uptake of GABA by potent and selective inhibitors of the GABA transporter enhances GABA activity. This property can be used therapeutically in for instance epilepsy or psychiatric disorders. In this paper putative structures of the GABA transporter, its mechanism of action, the progress made in the search for its amino acids involved in the binding of substrates and the SAR of inhibitors acting at the transporter will be discussed. To date only highly selective GAT-1 inhibitors are available. These compounds are lipophilic derivatives of (R)-nipecotic acid and guvacine. The most potent inhibitors of the cloned human GAT-1 are NNC-711 (IC50 = 0.04 mM) and tiagabine (IC50 = 0.07 mM). A diheteroarylvinyloxy analogue of tiagabine, 5 times more potent than tiagabine, has been reported recently. For the GAT-2, GAT-3 and BGT-1 subtypes only compounds with a small preference for one of the subtypes have been published.
Leiden/Amsterdam, Center for Drug Research, P.O. Box 9502, Leiden, 2300 RA, The Netherlands.
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D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D050485:GABA Plasma Membrane Transport Proteins; D006801:Humans; D007477:Ions; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D026901:Membrane Transport Proteins; D015394:Molecular Structure; D014179:Neurotransmitter Uptake Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D027361:Organic Anion Transporters; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; D007477:Ions; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; D027361:Organic Anion Transporters; C493413:SLC6A1 protein, human; C493416:SLC6A11 protein, human; C493418:SLC6A13 protein, human; D005680:gamma-Aminobutyric Acid