Design, Synthesis, and Pharmacology of Novel 7-Substituted 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of AMPA Receptors

• Published in: Journal of medicinal chemistry Vol. 50; no. 13; pp. 3153 - 3157
• Main Authors: Francotte, Pierre, de Tullio, Pascal, Goffin, Eric, Dintilhac, Gaëlle, Graindorge, Emmanuel, Fraikin, Pierre, Lestage, Pierre, Danober, Laurence, Thomas, Jean-Yves, Caignard, Daniel-Henri, Pirotte, Bernard
• Format: Journal Article Web Resource
• Language: English
• Published: WASHINGTON American Chemical Society 28.06.2007; Amer Chemical Soc
• Subjects: Allosteric Regulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - pharmacology; Animals; Benzothiadiazines; Biological and medical sciences; Chemistry; Chemistry, Medicinal; Chimie; Cognition - drug effects; Cyclic S-Oxides - chemical synthesis; Cyclic S-Oxides - chemistry; Cyclic S-Oxides - pharmacology; Drug Design; Electric Stimulation; Excitatory Postsynaptic Potentials; Glutamatergic system (aspartate and other excitatory aminoacids); Hippocampus - drug effects; Hippocampus - physiology; Human health sciences; In Vitro Techniques; Life Sciences & Biomedicine; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Norepinephrine - metabolism; Oocytes - drug effects; Oocytes - physiology; Pharmacie, pharmacologie & toxicologie; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pharmacy, pharmacology & toxicology; Physical, chemical, mathematical & earth Sciences; Physique, chimie, mathématiques & sciences de la terre; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Rats, Wistar; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; Recognition (Psychology) - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science & Technology; Sciences de la santé humaine; Structure-Activity Relationship; Thiadiazines - chemical synthesis; Thiadiazines - chemistry; Thiadiazines - pharmacology; Xenopus; HIPPOCAMPAL SLICES; MEMORY; CORTEX; DESENSITIZATION; RAT HIPPOCAMPAL; RESTORES OBJECT RECOGNITION; CYCLOTHIAZIDE; RELEASE; Rat; CNS stimulant; Psychotropic; Rodentia; Oral administration; Cognition; Pharmacology; Glutamate receptor; Vertebrata; AMPA receptor; Mammalia; Structure activity relation; Allosteric regulation; Animal; Organic fluorine compounds; Chemical synthesis
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm070120i

A series of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been synthesized and evaluated as potentiators of AMPA receptors. Attention was paid to the impact of the substituent introduced at the 7-position of the heterocycle. The biological evaluation was achieved by measuring the AMPA current in rat cortex mRNA-injected Xenopus oocytes. The most potent compound, 4-ethyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (12a) was found to be active in an object recognition test in rats demonstrating cognition enhancing effects in vivo after oral administration.