Mechanism of Inhibition of the GluA2 AMPA Receptor Channel Opening by Talampanel and Its Enantiomer: The Stereochemistry of the 4-Methyl Group on the Diazepine Ring of 2,3-Benzodiazepine Derivatives
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- 作者：Congzhou Wang ; Li Niu
- 刊名：ACS Chemical Neuroscience
- 出版年：2013
- 出版时间：April 17, 2013
- 年：2013
- 卷：4
- 期：4
- 页码：635-644
- 全文大小：360K
- 年卷期：v.4,no.4(April 17, 2013)
- ISSN：1948-7193
文摘
Stereoselectivity of 2,3-benzodiazepine compounds provides a unique way for the design of stereoisomers as more selective and more potent inhibitors as drug candidates for treatment of the neurological diseases involving excessive activity of AMPA receptors. Here we investigate a pair of enantiomers known as Talampanel and its (+) counterpart about their mechanism of inhibition and selectivity toward four AMPA receptor subunits or GluA1鈥?. We show that Talampanel is the eutomer with the endismic ratio being 14 for the closed-channel and 10 for the open-channel state of GluA2. Kinetic evidence supports that Talampanel is a noncompetitive inhibitor and it binds to the same site for those 2,3-benzodiazepine compounds with the C-4 methyl group on the diazepine ring. This site, which we term as the 鈥淢鈥?site, recognizes preferentially those 2,3-benzodiazepine compounds with the C-4 methyl group being in the R configuration, as in the chemical structure of Talampanel. Given that Talampanel inhibits GluA1 and GluA2, but is virtually ineffective on the GluA3 and GluA4 AMPA receptor subunits, we hypothesize that the 鈥淢鈥?site(s) on GluA1 and GluA2 to which Talampanel binds is different from that on GluA3 and GluA4. If the molecular properties of the AMPA receptors and Talampanel are used for selecting an inhibitor as a single drug candidate for controlling the activity of all AMPA receptors in vivo, Talampanel is not ideal. Our results further suggest that addition of longer acyl groups to the N-3 position should produce more potent 2,3-benzodiazepine inhibitors for the 鈥淢鈥?site.