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Issue 6, 2011
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New substituted aryl esters and aryl amides of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors

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Abstract

AMPA receptor potentiators belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been found to be of great interest as cognitive enhancers. Previous structure–activity relationships have demonstrated the importance for activity of the nature of the substituent at the 7-position of the heterocycle. This work aims to explore the impact on AMPA potentiation of the introduction of different aryl and aralkyl ester or aryl amide groups at the 7-position. The new synthesized compounds were evaluated as AMPA receptor potentiators by examining their effect on rat brain primary cell cultures on AMPA-evoked membrane depolarisation using fluorescent membrane potential dyes and on imaging-based plate reader. The most potent compound of this series was 2-methylphenyl 4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide 16c which provoked a strong potentiation of AMPA current with a potency close to that reported for the best reference compounds of the benzothiadiazine class (i.ecyclothiazide). This work also revealed that only the ortho-substitution of the phenyl group of 1,2,4-benzothiadiazine-7-carboxylate esters provided potent AMPA receptor potentiators opening the way to further chemical exploration.

Graphical abstract: New substituted aryl esters and aryl amides of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors

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Article information


Submitted
03 Mar 2011
Accepted
03 Mar 2011
First published
24 Mar 2011

Med. Chem. Commun., 2011,2, 509-523
Article type
Concise Article

New substituted aryl esters and aryl amides of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors

G. Dintilhac, D. Arslan, S. Dilly, L. Danober, I. Botez, P. Lestage, B. Pirotte and P. de Tullio, Med. Chem. Commun., 2011, 2, 509
DOI: 10.1039/C1MD00069A

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