title: 5-Arylbenzothiadiazine Type Compounds as Positive Allosteric Modulators of AMPA/Kainate Receptors.
abstract: The potential therapeutic benefit of compounds able to activate AMPA receptors (AMPAr) has led to the search for new AMPAr positive modulators. On the basis of crystallographic data of the benzothiadiazines binding mode in the S1S2 GluA2 dimer interface, a set of 5-aryl-2,3-dihydrobenzothiadiazine type compounds has been synthesized and tested. Electrophysiological results suggested that 5-heteroaryl substituents on the benzothiadiazine core like 3-furanyl and 3-thiophenyl dramatically enhance the activity as positive modulators of AMPAr with respect to IDRA21 and cyclothiazide. Mouse brain microdialysis studies have suggested that 7-chloro-5-(3-furyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide crosses the blood-brain barrier after intraperitoneal injection. Biological results have been rationalized by a computational docking simulation that it has currently employed to design new AMPAr-positive modulator candidates.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia , Via Campi 183, 41125 Modena, Italy.
authors.forename: Umberto M
authors.initials: UM
authors.lastname: Battisti
authors.affiliation: Laboratory of Medicinal Chemistry and Neuroengineering, Department of Chemistry, Medical University of Lublin , ul. W. Chodzki 4a, 20-093 Lublin, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia , Via Campi 183, 41125 Modena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cannazza
authors.affiliation: Dipartimento di Scienze Biomediche, Università degli Studi di Modena e Reggio Emilia , Via Campi 287, 41125 Modena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Puia
authors.affiliation: Dipartimento di Scienze Biomediche, Università degli Studi di Modena e Reggio Emilia , Via Campi 287, 41125 Modena, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Stocca
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia , Via Campi 183, 41125 Modena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Braghiroli
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia , Via Campi 183, 41125 Modena, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Parenti
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia , Via Campi 183, 41125 Modena, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Brasili
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento , Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy.
authors.forename: Marina M
authors.initials: MM
authors.lastname: Carrozzo
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento , Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Citti
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento , Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy.
authors.forename: Luigino
authors.initials: L
authors.lastname: Troisi
keywords: AMPA modulators; IDRA21; benzothiadiazines; cognitive enhancers