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Development of thiophenic analogues of benzothiadiazine dioxides as new powerful potentiators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2013 Oct 24; Vol. 56 (20), pp. 7838-50. Date of Electronic Publication: 2013 Oct 03. - Publication Year :
- 2013
-
Abstract
- On the basis of the results obtained in previous series of AMPA potentiators belonging to 3,4-dihydro-2H-benzo- and 3,4-dihydro-2H-pyrido-1,2,4-thiadiazine 1,1-dioxides, the present work focuses on the design of original isosteric 3,4-dihydro-2H-thieno-1,2,4-thiadiazine 1,1-dioxides. Owing to the sulfur position, three series of compounds were developed and their activity as AMPA potentiators was characterized. In each of the developed series, potent compounds were discovered. After screening the selected active compounds on a safety in vivo test, 6-chloro-4-ethyl-3,4-dihydro-2H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-dioxide (24) appeared as the most promising compound and was further evaluated. Its effects on long-term potentiation in vivo and on AMPA-mediated noradrenaline release were measured to predict its potential cognitive enhancing properties. Finally, an object recognition test performed in mice revealed that 24 was able to significantly enhance cognition, after oral administration, at doses as low as 0.3 mg/kg. This study validates the interest of the isosteric replacement of the benzene or pyridine nuclei by the thiophene nucleus in the ring-fused thiadiazine dioxides class of AMPA potentiators.
- Subjects :
- Animals
Benzothiadiazines chemistry
Cells, Cultured
Cognition drug effects
Cyclic S-Oxides chemical synthesis
Cyclic S-Oxides chemistry
Cyclic S-Oxides pharmacology
Diazoxide chemistry
Drug Design
Excitatory Amino Acid Agonists chemical synthesis
Excitatory Amino Acid Agonists chemistry
Excitatory Postsynaptic Potentials drug effects
Female
Hippocampus drug effects
Hippocampus physiology
Long-Term Potentiation drug effects
Membrane Potentials drug effects
Mice
Models, Chemical
Molecular Structure
Norepinephrine metabolism
Oocytes drug effects
Oocytes metabolism
Rats
Receptors, AMPA metabolism
Thiadiazines chemical synthesis
Thiadiazines chemistry
Thiadiazines pharmacology
Thiophenes chemistry
Xenopus laevis
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid pharmacology
Benzothiadiazines pharmacology
Diazoxide pharmacology
Excitatory Amino Acid Agonists pharmacology
Receptors, AMPA agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 56
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24090223
- Full Text :
- https://doi.org/10.1021/jm400676g