We review the neurochemical and behavioral profile of the selective
gamma-aminobutyric acid (
GABA) uptake inhibitor, (R)-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl)
nipecotic acid hydrochloride [
tiagabine (TGB), previously termed NNC 05-0328, NO 05-0328, and
NO-328], which is currently in phase III clinical trials for
epilepsy. TGB is a potent, and specific
GABA uptake inhibitor. TGB lacks significant affinity for other
neurotransmitter receptor binding sites and/or uptake sites. In electrophysiological experiments in hippocampal slices in culture, TGB prolonged the inhibitory postsynaptic potentials (IPSP) and inhibitory postsynaptic currents (IPSC) in the CA1 and CA3 produced by the addition of exogenous
GABA. In vivo microdialysis shows that TGB also increases extracellular
GABA overflow in a dose-dependent manner. Together these biochemical data suggest that the in vitro and in vivo mechanism of action of TGB is to inhibit
GABA uptake specifically, resulting in an increase in GABAergic mediated inhibition in the brain. TGB is a potent
anticonvulsant agent against methyl-6,7-dimethyoxy-4-ethyl-B-carboline-3-carboxylate (
DMCM)-induced clonic convulsions (mice), subcutaneous
pentylenetetrazol (PTZ)-induced tonic convulsions (mice and rats), sound-induced convulsions in DBA/2 mice and genetically
epilepsy-prone rats (GEPR), and electrically induced convulsions in kindled rats. TGB is partially efficacious, against subcutaneous PTZ-induced clonic convulsions, and photically induced
myoclonus in Papio papio. TGB is weakly efficacious in the intravenous PTZ seizure threshold test and the maximal electroshock seizure (MES) test and produces only partial protection against
bicuculline (
BIC)-induced convulsions in rats. The overall biochemical and
anticonvulsant profile of TGB suggests potential utility in the treatment of chronic
seizure disorders such as generalized clonic-
tonic epilepsy (GTCS), photomyoclonic
seizures, myoclonic
petit mal epilepsy, and
complex partial epilepsy.