5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of AMPA receptor (AMPA-PAMs) have received particular attention in the last decade for their nootropic activity and lack of the excitotoxic side effects of direct agonists. Recently, our research group has published the synthesis and biological activity of 7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (1), one of the most active benzothiadiazine-derived AMPA-PAMs in vitro to date. However, 1 exists as two stereolabile enantiomers, which rapidly racemise in physiological conditions and only one isomer is responsible for the pharmacological activity. In the present work, experiments carried out with rat liver microsomes show that 1 is converted by hepatic cytochrome P450 to the corresponding unsaturated derivative 2 and to the corresponding pharmacologically inactive benzenesulfonamide 3. Surprisingly, patch-clamp experiments reveal that 2 displays an activity comparable to that of the parent compound. Molecular modelling studies were performed to rationalize these results. Furthermore, mice cerebral microdialysis studies suggest that 2 is able to cross the blood brain barrier and increases acetylcholine and serotonin levels in the hippocampus. The experimental data disclose that the achiral hepatic metabolite 2 possesses the same pharmacological activity of its parent compound 1, but with an enhanced chemical and stereochemical stability, as well as an improved pharmacokinetic profile compared to 1.

7-chloro-5-(furan-3-yl)-3-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide as positive allosteric modulator of AMPA receptor. The end of the unsaturated-inactive paradigm? / Citti, Cinzia; Battisti, UMBERTO MARIA; Cannazza, Giuseppe; Jozwiak, Krzysztof; Stasiak, Natalia; Puja, Giulia; Ravazzini, Federica; Ciccarella, Giuseppe; Braghiroli, Daniela; Parenti, Carlo; Troisi, Luigino; Zoli, Michele. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - 4:(2015), pp. 231-236. [10.1021/acschemneuro.5b00257]

7-chloro-5-(furan-3-yl)-3-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide as positive allosteric modulator of AMPA receptor. The end of the unsaturated-inactive paradigm?

BATTISTI, UMBERTO MARIA;CANNAZZA, Giuseppe;PUJA, Giulia;RAVAZZINI, FEDERICA;BRAGHIROLI, Daniela;PARENTI, Carlo;ZOLI, Michele
2015

Abstract

5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of AMPA receptor (AMPA-PAMs) have received particular attention in the last decade for their nootropic activity and lack of the excitotoxic side effects of direct agonists. Recently, our research group has published the synthesis and biological activity of 7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (1), one of the most active benzothiadiazine-derived AMPA-PAMs in vitro to date. However, 1 exists as two stereolabile enantiomers, which rapidly racemise in physiological conditions and only one isomer is responsible for the pharmacological activity. In the present work, experiments carried out with rat liver microsomes show that 1 is converted by hepatic cytochrome P450 to the corresponding unsaturated derivative 2 and to the corresponding pharmacologically inactive benzenesulfonamide 3. Surprisingly, patch-clamp experiments reveal that 2 displays an activity comparable to that of the parent compound. Molecular modelling studies were performed to rationalize these results. Furthermore, mice cerebral microdialysis studies suggest that 2 is able to cross the blood brain barrier and increases acetylcholine and serotonin levels in the hippocampus. The experimental data disclose that the achiral hepatic metabolite 2 possesses the same pharmacological activity of its parent compound 1, but with an enhanced chemical and stereochemical stability, as well as an improved pharmacokinetic profile compared to 1.
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7-chloro-5-(furan-3-yl)-3-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide as positive allosteric modulator of AMPA receptor. The end of the unsaturated-inactive paradigm? / Citti, Cinzia; Battisti, UMBERTO MARIA; Cannazza, Giuseppe; Jozwiak, Krzysztof; Stasiak, Natalia; Puja, Giulia; Ravazzini, Federica; Ciccarella, Giuseppe; Braghiroli, Daniela; Parenti, Carlo; Troisi, Luigino; Zoli, Michele. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - 4:(2015), pp. 231-236. [10.1021/acschemneuro.5b00257]
Citti, Cinzia; Battisti, UMBERTO MARIA; Cannazza, Giuseppe; Jozwiak, Krzysztof; Stasiak, Natalia; Puja, Giulia; Ravazzini, Federica; Ciccarella, Giuseppe; Braghiroli, Daniela; Parenti, Carlo; Troisi, Luigino; Zoli, Michele
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1074962
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