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Issue 12, 2016
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An unexpected reversal in the pharmacological stereoselectivity of benzothiadiazine AMPA positive allosteric modulators

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Abstract

Benzothiadiazine type compounds (BTDs) have gained great attention for their potential therapeutic activity as nootropic and neuroprotective agents. BTDs, acting as AMPA positive allosteric modulators, potentiate the glutamatergic neurotransmission without the side effects typically associated with direct agonists. Studies regarding the binding mode of racemic BTDs into the receptor binding pocket demonstrated that one enantiomer establishes a more favourable interaction and possesses a higher biological activity with respect to the other one. The S enantiomer was proved to be the eutomer for both IDRA21 and S18986, two of the most studied BTD AMPA positive allosteric modulators. However, recent data highlighted an opposite stereoselectivity for some substituted BTDs (7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide and 7-chloro-2,3,4-trimethyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide) showing unexpected structure–activity relationships. In this work, the synthesis and configuration assignment of the stereoisomers of 7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, one of the most active BTDs, are reported. Electrophysiological tests demonstrated that the R form is the eutomer. Docking and molecular dynamics simulations on the AMPA GluA2 binding site revealed new insights into the stereodiscrimination process. Lastly, metabolic studies disclosed a stereoselective hepatic metabolization of this chiral BTD.

Graphical abstract: An unexpected reversal in the pharmacological stereoselectivity of benzothiadiazine AMPA positive allosteric modulators

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Publication details

The article was received on 01 Aug 2016, accepted on 26 Sep 2016 and first published on 28 Sep 2016


Article type: Research Article
DOI: 10.1039/C6MD00440G
Citation: Med. Chem. Commun., 2016,7, 2410-2417
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    An unexpected reversal in the pharmacological stereoselectivity of benzothiadiazine AMPA positive allosteric modulators

    U. M. Battisti, C. Citti, G. Rastelli, L. Pinzi, G. Puja, F. Ravazzini, G. Ciccarella, D. Braghiroli and G. Cannazza, Med. Chem. Commun., 2016, 7, 2410
    DOI: 10.1039/C6MD00440G

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