The GABA Transporter and its Inhibitors
Abstract: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 high 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 uM) and tiagabine (IC50 = 0.07 uM). 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.
Keywords: GABA activity; GABA transporter; GAT-1 subtype; GAT-2 subtype; GAT-3 subtype; Guvacine; Inhibitory neurotransmitter; Ion-dependency; Isoguvacine; Isonipecotic acid; Nipecotic acid; Psychiatric disorders
Document Type: Review Article
Publication date: October 1, 2000
- Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.