RESEARCH MONOGRAPH · KDC-MN-247
Tiagabine
Tiagabine (Gabitril) is a selective inhibitor of the GAT-1 GABA transporter, the protein that pulls GABA back into nerve cells after release. By blocking GAT-1, the drug prolongs the time GABA remains in the synapse and amplifies inhibitory signaling. It was approved by the FDA in 1997 as add-on therapy for partial seizures. Clinical adoption was modest because it does not work well as monotherapy and has a narrow effective dose window. It saw some off-label use for anxiety and sleep, but a paradoxical risk of inducing seizures in patients without epilepsy when used at off-label doses earned it an FDA warning in 2005. Mostly a research tool now for studying GABA transporter pharmacology. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
GAT-1 selective GABA reuptake inhibitor
A nipecotic acid derivative selective GABA reuptake inhibitor; the prototype GAT-1 transporter blocker.
Abstract
Tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid; CAS 115103-54-3; molecular formula C20H25NO2S2; molecular weight 375.55) is a nipecotic acid derivative selective inhibitor of the GABA transporter GAT-1, developed at Novo Nordisk and approved by the FDA in 1997 under the trade name Gabitril. Mechanism: high-affinity inhibition of GAT-1 (the principal neuronal GABA reuptake transporter) prolongs synaptic GABA availability after release, enhancing GABA-A and GABA-B receptor activation. Selectivity for GAT-1 over GAT-2 and GAT-3 is greater than 100-fold. Plasma half-life is 7 to 9 hours; metabolism is via CYP3A4. Approved as adjunctive therapy in partial-onset seizures in patients aged 12 and older. Off-label use in generalized anxiety disorder has been complicated by FDA warnings of new-onset seizures in patients without epilepsy (incidence approximately 1 percent at off-label doses). Used as the canonical GAT-1 selective inhibitor in mechanism studies.
Mechanism of action
Selective inhibition of the GAT-1 GABA transporter (greater than 100-fold over GAT-2/GAT-3). Prolongs synaptic GABA after release.
Reported research dose ranges
Clinical 32 to 56 mg per oral administration daily, in divided doses. Rodent studies 5 to 30 mg/kg/day.
References
- Borden LA, et al. Tiagabine, SK&F 89976-A, CI-966, and NNC-711 are selective for the cloned GABA transporter GAT-1. Eur J Pharmacol 1994.
- Suzdak PD, Jansen JA. A review of the preclinical pharmacology of tiagabine. Epilepsia 1995.
- Krogsgaard-Larsen P, et al. GABA uptake inhibitors. Design, molecular pharmacology and therapeutic aspects. Curr Pharm Des 2000.
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FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.