title: 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.
abstract: 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.
authors.affiliation: Drug Research Center, Laboratoire de Chimie Pharmaceutique, Université de Liège, Av. de l'Hôpital, 1, B36, 4000 Liège, Belgium. pierre.francotte@ulg.ac.be
authors.forename: Pierre
authors.initials: P
authors.lastname: Francotte
authors.forename: Pascal de
authors.initials: Pd
authors.lastname: Tullio
authors.forename: Eric
authors.initials: E
authors.lastname: Goffin
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Dintilhac
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Graindorge
authors.forename: Pierre
authors.initials: P
authors.lastname: Fraikin
authors.forename: Pierre
authors.initials: P
authors.lastname: Lestage
authors.forename: Laurence
authors.initials: L
authors.lastname: Danober
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Thomas
authors.forename: Daniel-Henri
authors.initials: DH
authors.lastname: Caignard
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001581:Benzothiadiazines; D003071:Cognition / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D009638:Norepinephrine / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014981:Xenopus; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: C531043:4-ethyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide; D001581:Benzothiadiazines; D003499:Cyclic S-Oxides; D012333:RNA, Messenger; D018091:Receptors, AMPA; D013829:Thiadiazines; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D009638:Norepinephrine