title: Structure-activity relationships of selective GABA uptake inhibitors.
abstract: For more than four decades there has been a search for selective inhibitors of GABA transporters. This has led to potent and selective inhibitors of the cloned GABA transporter subtype GAT1, which is responsible for a majority of neuronal GABA transport. The only clinically approved compound with this mechanism of action is Tiagabine. Other GABA transporter subtypes have not been targeted with comparable selectivity and potency. We here review a comprehensive series of competitive inhibitors that provide information about the GABA recognition site and summarise the structure-activity relations in a ligand-based pharmacophore model that suggests how future compounds could be designed. Finally, some of the recent results on subtype-characterised competitive inhibitors and recent lipophilic aromatic GABA uptake inhibitors are reviewed.
authors.affiliation: Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark.
authors.forename: Signe
authors.initials: S
authors.lastname: Høg
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Greenwood
authors.forename: Karsten B
authors.initials: KB
authors.lastname: Madsen
authors.forename: Orla M
authors.initials: OM
authors.lastname: Larsson
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
authors.forename: Arne
authors.initials: A
authors.lastname: Schousboe
authors.forename: Povl
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: Rasmus P
authors.initials: RP
authors.lastname: Clausen
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology; D018755:GABA Agonists / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D018755:GABA Agonists