Chemical Properties
Off-White Crystalline Solid
Uses
An inhibitor of NOS1, AChR, cytochrome P-450, and KIR6.1.
Uses
Cytochrome P-459 inhibitor; blocks glibenclamide-sensitive K+ channels; inhibits neuronal nitric oxide synthetase; stimulates endothelial cell prostacyclin while inhibiting platelet thromboxane synthesis
Description
SKF 525A is a widely used, nonspecific cytochrome P (CYP)450 inhibitor that demonstrates 100% inhibition of the various CYP450 isoforms at 1-100 μM. It therefore potentiates the effects of many different drugs by inhibiting their metabolism (IC50 values in the μM range when tested using human liver microsomes). SKF 525A inhibits CYP450-dependent arachidonic acid conversion to active EET metabolites, antagonizing the recovery of functional calcium pools. It also acts as a noncompetitive inhibitor of acetylcholine nicotinic receptors (IC50 = 19 μM in mouse skeletal muscle).
Safety Profile
Poison by intraperitoneal, subcutaneous, and intravenous routes. Moderately toxic by ingestion. Experimental reproductive effects. When heated to decomposition it emits very toxic fumes of NOx and HCl.
in vitro
previous study found that when incubated with human liver microsomes, skf525a could undergo cyp-dependent oxidative n-deethylation to its secondary amine metabolite skf8742. in addition, skf525a and its metabolite and primary amine analog all inhibited cyp2b6-, cyp2c9-, cyp2c19-, cyp2d6-, as well as cyp3a-selective reactions to various degrees but had little effect on cyp1a2, cyp2a6, and cyp2e1 reactions [1].
in vivo
animal study found that skf 525a at 1.5-9 mg/kg could reduce or abolish the hypertensive effect of mcn-a-343, dmpp and nicotine, but could neither noticeably affect the hypertensive effect of tyramine, adrenaline and noradrenaline, nor the hypotensive effect of acetylcholine and orciprenaline. thus, skf 525a was able to block the rat sympathetic ganglia and the adrenal medulla and such blockade was non-specific. moreover, the blockade might result from the stabilizing effect of skf 525a on postsynaptic membranes of the sympathetic ganglia and the adrenal medulla [2].
IC 50
in the μm range when tested using human liver microsomes
References
1) Franklin and Hathaway (2008)?2-Diethylaminoethyl-2,2-diphenylvalerate-HCL (SKF525A) revisited: comparative cytochrome P450 inhibition in human liver microsomes by SKF525A, its metabolites, and SKF-acid and SKF-alcohol;?Drug Metab. Dispos,?36?2539
2) Suarez-Kurtz and Bianchi (1970)?Sites of action of SKF-525A in nerve and muscle;?J. Pharmacol. Exp. Ther.,?172?33
3) Spitzmaul?et al. (2009)?The local anesthetics proadifen and adiphenine inhibit nicotinic receptors by different molecular mechanisms; Br. J. Pharmacol.,?157?804
4) Prince and Sine (1999)?Acetylcholine and epibatidine binding to muscle acetylcholine receptors distinguish between concerted and uncoupled models; J. Biol. Chem.,?274?19623
5) Sakust and Yoneda (1994)?Inhibition by SKF 525A and quinacrine of endogenous glibenclamide-sensitive K+ channels in follicle-enclosed Xenopus oocytes; Eur. J. Pharmacol.,?252?117
