Structure-activity relationships of selective GABA uptake inhibitors.
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.
Høg
Signe
S
Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark.
Greenwood
Jeremy R
JR
Madsen
Karsten B
KB
Larsson
Orla M
OM
Frølund
Bente
B
Schousboe
Arne
A
Krogsgaard-Larsen
Povl
P
Clausen
Rasmus P
RP
D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology; D018755:GABA Agonists / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D018755:GABA Agonists