title: 7-Chloro-5-(furan-3-yl)-3-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-Dioxide as Positive Allosteric Modulator of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor. The End of the Unsaturated-Inactive Paradigm?
abstract: 5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-PAMs) have received particular attention in the past 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 racemize 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 modeling 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 with 1.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento , Via per Monteroni, 73100 Lecce, Italy.|CNR NANOTEC, Campus Ecoteckne dell'Università del Salento , Via per Monteroni, 73100 Lecce, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Citti
authors.affiliation: Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia , Via Campi 103, 41125 Modena, Italy.|Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Umberto M
authors.initials: UM
authors.lastname: Battisti
authors.affiliation: CNR NANOTEC, Campus Ecoteckne dell'Università del Salento , Via per Monteroni, 73100 Lecce, Italy.|Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia , Via Campi 103, 41125 Modena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cannazza
authors.affiliation: Laboratory of Biopharmacy, 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 della Vita, Università di Modena e Reggio Emilia , Via Campi 103, 41125 Modena, Italy.
authors.forename: Natalia
authors.initials: N
authors.lastname: Stasiak
authors.affiliation: Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia , Via Campi 103, 41125 Modena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Puja
authors.affiliation: Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia , Via Campi 103, 41125 Modena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Ravazzini
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento , Via per Monteroni, 73100 Lecce, Italy.|CNR NANOTEC, Campus Ecoteckne dell'Università del Salento , Via per Monteroni, 73100 Lecce, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ciccarella
authors.affiliation: Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia , Via Campi 103, 41125 Modena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Braghiroli
authors.affiliation: Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia , Via Campi 103, 41125 Modena, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Parenti
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento , Via per Monteroni, 73100 Lecce, Italy.
authors.forename: Luigino
authors.initials: L
authors.lastname: Troisi
authors.affiliation: Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze, Università di Modena e Reggio Emilia , Via Campi 287, 41125 Modena, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Zoli
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003342:Corpus Striatum / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry* / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D017551:Microdialysis; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry; D013829:Thiadiazines / Q000737:chemistry / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C000612082:7-chloro-5-(furan-3-yl)-3-methyl-4H-benzo(e)(1,2,4)thiadiazine 1,1-dioxide; D018690:Excitatory Amino Acid Agonists; D005663:Furans; D018377:Neurotransmitter Agents; D018091:Receptors, AMPA; D013829:Thiadiazines; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
keywords: AMPA receptor; benzothiadiazines; central nervous system; hepatic metabolism; microdialysis; neurotransmitters