- Carbamazepine derivatives with P2X4 receptor-blocking activity
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Antagonists for the P2 receptor subtype P2X4, an ATP-activated cation channel receptor, have potential as novel drugs for the treatment of neuropathic pain and other inflammatory diseases In the present study, a series of 47 carbamazepine derivatives including 32 novel compounds were designed, synthesized, and evaluated as P2X4 receptor antagonists Their potency to inhibit ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with the human P2X4 receptor was determined Additionally, species selectivity (human, rat, mouse) and receptor subtype selectivity (P2X4 vs P2X1, 2, 3, 7) were investigated for selected derivatives The most potent compound of the present series, which exhibited an allosteric mechanism of P2X4 inhibition, was N,N-diisopropyl-5H-dibenz[b,f]azepine-5-carboxamide (34, IC50 of 3.44 μM) The present study extends the so far very limited knowledge on structure-activity relationships of P2X4 receptor antagonists
- Tian, Maoqun,Abdelrahman, Aliaa,Weinhausen, Stephanie,Hinz, Sonja,Weyer, Stefanie,Dosa, Stefan,El-Tayeb, Ali,Müller, Christa E.
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supporting information
p. 1077 - 1088
(2014/02/14)
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- Antibodies specific to carbamazepine
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The present disclosure is directed to antibodies specific to carbamazepine, immunogens used to produce the antibodies, and immunoassay kits and methods for using the antibodies.
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Page/Page column 6; 8; 9
(2013/11/05)
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- Detection of 2-hydroxyiminostilbene in the urine of patients taking carbamazepine and its oxidation to a reactive iminoquinone intermediate
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Carbamazepine is one of the most widely used anticonvulsants in North America; however, its use is associated with a range of serious idiosyncratic adverse reactions. These reactions are thought to result from the formation of chemically reactive metabolites. Carbamazepine is extensively metabolized in the liver and one of the major metabolites is 2-hydroxycarbamazepine, which has previously been detected as a urinary metabolite excreted by rats and humans along with its further metabolized product, 2- hydroxyiminostilbene. In this study, we found that the urine of patients taking carbamazepine appeared to contain more of the glucuronide of 2- hydroxyiminostilbene than that of 2-hydroxycarbamazepine. We have also demonstrated that 2-hydroxyiminostilbene can be oxidized readily to an iminoquinone species by HOCl, H2O2 or even on exposure to air. The reactivity of this iminoquinone as an electrophile was studied. It was shown to react with sulfhydryl-containing nucleophiles, such as glutathione and N- acetylcysteine. We also found a metabolite with the same molecular weight as 4-methylthio-2-hydroxyiminostilbene, but not the corresponding carbamazepine derivative, in the urine of patients taking carbamazepine and this presumably reflects the formation of a glutathione conjugate of the reactive iminoquinone. This iminoquinone intermediate may play a role in carbamazepine-induced idiosyncratic reactions.
- Ju,Uetrecht,Van Koppen, Chris J.
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