A Review of the Preclinical Pharmacology of Tiagabine: A Potent and Selective Anticonvulsant GABA Uptake Inhibitor

Summary: We review the neurochemical and behavioral profile of the selective γ‐aminobutyric acid (GABA) up‐take 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 in‐creases 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‐dimethyox‐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.

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