SKF 87699A hydrochloride 是一种选择性 GABA 转运蛋白 (GAT-1) 抑制剂，对 CHO 细胞中的 GAT-1、GAT-2 和 GAT-3 的 IC50 分别为 0.28 μM、137.34 μM 和 202.8 μM。
SKF89976A hydrochloride is a selective GABA transporter (GAT-1) inhibitor with IC50s of 0.28 μM, 137.34 μM and 202.8 μM for GAT-1, GAT-2 and GAT-3 in CHO cells, respectively.
SKF89976A has a weak antiallodynic action. SKF89976A weakly inhibits serotonin transporter (SERT), noradrenaline transporter (NET), and dopamine transporter (DAT) in chinese hamster ovary (CHO) cells stably expressing each transporter using a substrate uptake assay, with IC50 values of 3514 , 202.13, and 728.8, respectively[1]. SKF89976A is a GABA-transport blocker. GABA (1 mM) elicited an inward current that is completely suppressed by the GABA transport inhibitors tiagabine (10 μM) and SKF89976A (100 μM), but is unaffected by 100 μM picrotoxin. 100 μM SKF 89976-A is known to block the transport of GABA into cells, completely eliminated the GABA-elicited current in a reversible fashion[2]. SKF89976A is a nontransportable blockers of GAT-1. SKF89976-A also suppresses baseline inward currents that likely result from tonic GAT activation by background GABA. SKF89976A (100 μM) reversibly reduces GAT currents in every studied cell by 67.9±4.4% (n=19). Intracellular perfusion of 20 μM SKF89976-A progressively reduced and blocked GABA-induced GAT currents without blocking GABAAR-mediated currents (n=4)[3].
SKF89976A produces a weak antiallodynic response when administered i.v. (0.3 mg/kg). The i.t. injection of SKF89976A dose-dependently ameliorates the reduction in the withdrawal threshold in PSL model mice[1].
参考文献:
[1]. Jinzenji A, et al. Antiallodynic action of 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), a betaine/GABA transporter inhibitor. J Pharmacol Sci. 2014;125(2):217-26.
[2]. Kreitzer MA, et al. Glutamate modulation of GABA transport in retinal horizontal cells of the skate. J Physiol. 2003 Feb 1;546(Pt 3):717-31.
[3]. Barakat L, et al. GAT-1 and reversible GABA transport in Bergmann glia in slices. J Neurophysiol. 2002 Sep;88(3):1407-19.
Cell experiment: | CHO cells stably expressing the mouse GAT subtypes, rat serotonin transporter (SERT), rat noradrenaline transporter (NET), and rat dopamine transporter (DAT) are incubated with 10 nM tritium-labeled GABA or monoamines for 10 min in the absence or presence of various concentrations of the GAT inhibitors (e.g., SKF89976A) tested. Values presented for SERT, NET, and DAT are the mean±S.E.M. for 3 experiments, with each being performed in duplicate[1]. |
Animal experiment: | Mice[1]5-week-old ddY male mice, weighing 25-30 g at the beginning of the study are used. Mice are administered NNC05-2090, SKF89976A (0.3 mg/kg, i.p.), (S)-SNAP5114, or amitriptyline. The composition of ACSF (in mM) is 142 mM NaCl, 5 mM KCl, 2 mM CaCl2, 2 mM MgCl2, 1.25 mM NaH2PO4, 10 mM d-glucose, 10 mM HEPES, and 0.05% fatty acid-free bovine serum albumin (pH 7.4). The intraperitoneal (i.p.) injection of drugs is administered in a volume of 0.1 mL/10 g body weight. When given intravenously (i.v.), solutions are injected into the tail vein in a volume of 0.1 mL/10 g body weight. The head of a mouse is placed into a plastic cap and the body is held with one hand for an intrathecal (i.t.) injection. A 27-gauge needle attached to a Hamilton microsyringe is inserted into the subarachnoid space between the L5 and L6 vertebrae of the conscious mouse and 5 mL of the drug solution is slowly injected[1]. |
参考文献: [1]. Jinzenji A, et al. Antiallodynic action of 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), a betaine/GABA transporter inhibitor. J Pharmacol Sci. 2014;125(2):217-26. | |
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