title: 1,2,4-Benzothiadiazine-1,1-dioxide derivatives as ionotropic glutamate receptor ligands: synthesis and structure-activity relationships.
abstract: Ionotropic glutamate receptor (iGluR) modulators, specially AMPA receptor antagonists, are potential tools for numerous therapeutic applications in neurological disorders, including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, epilepsy, chronic pain, and neuropathology ensuing from cerebral ischemia or cardiac arrest. In this work, the synthesis and binding affinities at the Gly/NMDA, AMPA, and kainic acid (KA) receptors of a new series of 1,2,4-benzothiadiazine-1,1-dioxide derivatives are reported. The results show that 1,2,4-benzothiadiazine-1,1-dioxide is a new scaffold for obtaining iGluR ligands. Moreover, this work has led us to the 7-(3-formylpyrrol-1-yl)-6-trifluoromethyl substituted compound 7, which displays the highest AMPA receptor affinity and high selectivity versus the Gly/NMDA (90-fold) and KA (46-fold) receptors.
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Sesto Fiorentino, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Varano
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
authors.forename: Lucia
authors.initials: L
authors.lastname: Squarcialupi
authors.forename: Rosanna
authors.initials: R
authors.lastname: Matucci
mesh_terms: D000818:Animals; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D018683:Excitatory Amino Acid Agents / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D015394:Molecular Structure; D011485:Protein Binding; D051381:Rats; D058468:Receptors, Ionotropic Glutamate / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001581:Benzothiadiazines; D018683:Excitatory Amino Acid Agents; D008024:Ligands; D058468:Receptors, Ionotropic Glutamate
keywords: 1,2,4-Benzothiadiazine-1,1-dioxide; AMPA receptor; AMPA receptor antagonists; Ionotropic glutamate receptors; Neurological diseases