CI-966

CI-966 is a potent, selective, orally active and brain-penetrant inhibitor of the GABA transporter GAT-1, with IC₅₀s of 0.26 μM and 1.2 μM for hGAT-1, rGAT-1, respectively. CI-966 shows more than 200-fold selectivity over GAT-2, GAT-3, and BGT-3. CI-966 exhibits anticonvulsant and neuroprotective activities^[1][2][3]. IC50 & Target: IC50: 0.26 μM (hGAT-1); 1.2 μM (rGAT-1); 297 μM (rGAT-2); 333 μM (hGAT-3); 1140 μM (rGAT-3); 300 μM (hBGT-3)^[1] In Vitro: CI-966 functions by selectively inhibiting GABA reuptake in neurons and glial cells^[4]. In Vivo: CI-966 produces intermediate levels of Pentylenetetrazol (PTZ)-lever responding when administered to PTZ-trained rats^[4].
CI-966 enhances gamma-aminobutyric acid action in CA1 pyramidal layer in situ. CI-966 is administered systemically by i.p. injection (5 mg/kg) in Sprague-Dawley rats under urethane anaesthesia. Twenty to thirty minutes after injection there is a highly variable, but overall significant, enhancement of the inhibition of hippocampal population spikes by GABA applied by microiontophoresis in the CA1 region^[5].
CI-966 exhibits anticonvulsant properties in various animal models. Oral absorption of CI-966 in dogs given 1.39 mg/kg is rapid with a t_max of 0.7 hr. In rats given 5 mg/kg oral, a mean t_max of 4.0 hr is observed. Following i.v. administration of the same respective doses, elimination t_1/2 in dogs and rats averages 1.2 and 4.5 hr. Absolute oral bioavailability of CI-966 is 100% in both species^[6].