SKF 89976A hydrochloride is a potent inhibitor of GABA uptake with IC50 of 0.13, 550, 944 and 7210 μM for hGAT-1, rGAT-2, hGAT-3 and hBGT-1 respectively. GABA transporter subtype 1 (GAT-1) and GABA transporter subtype 3 (GAT-3) are the main transporters that regulate inhibitory GABAergic transmission in the mammalian brain through GABA reuptake. GAT-1 inhibitor SKF 89976A significantly prolonged the decay time, but did not affect the amplitude, of eIPSCs induced by striatal stimulation (15-20 V). Furthermore, SKF 89976A blockade also increased the amplitude and frequency of spontaneous IPSCs, but did not affect miniature IPSCs. SKF 89976A inhibits transport current competitively (Ki = 7 μM) and transmitter-gated current non-competitively (Ki = 0.03 nM). In vivo, SKF 89976A is able to pass the blood-brain barrier after systemic administration and is active.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
Differential localization and function of GABA transporters, GAT-1 and GAT-3, in the rat globus pallidus.
Jin XT, et al. Eur J Neurosci. 2011 Apr;33(8):1504-18. PMID: 21410779.
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