title: Synthesis and Pharmacology of Mono-, Di-, and Trialkyl-Substituted 7-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides Combined with X-ray Structure Analysis to Understand the Unexpected Structure-Activity Relationship at AMPA Receptors.
abstract: Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA)-type ionotropic glutamate receptors are promising compounds for treatment of neurological disorders, for example, Alzheimer's disease. Here, we report synthesis and pharmacological evaluation of a series of mono-, di-, or trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides, comprising in total 16 new modulators. The trisubstituted compounds 7b, 7d, and 7e revealed potent activity (EC2× = 2.7-4.3 μM; concentration of compound responsible for a 2-fold increase of the AMPA mediated response) as AMPA receptor potentiators in an in vitro cellular fluorescence assay (FLIPR). The 4-cyclopropyl compound 7f was found to be considerably less potent (EC2× = 60 μM), in contrast to previously described 4-monoalkyl-substituted benzothiadiazine dioxides for which the cyclopropyl group constitutes the best choice of substituent. 7b was subjected to X-ray structural analysis in complex with the GluA2 ligand-binding domain. We propose an explanation of the unexpected structure-activity relationship of this new series of mono-, di-, and trialkyl-substituted 1,2,4-benzothiadiazine 1,1-dioxide compounds. The methyl substituent in the 3-position directs the binding mode of the 1,2,4-benzothiadiazine 1,1-dioxide (BTD) scaffold. When a methyl substituent is present in the 3-position of the BTD, additional methyl substituents in both the 2- and 4-positions increase potency, whereas introduction of a 4-cyclopropyl group does not enhance potency of 2,3,4-alkyl-substituted BTDs. A hydrogen bond donor in the 2-position of the BTD is not necessary for modulator potency.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken, 2, DK-2100 Copenhagen, Denmark.
authors.forename: Anja Probst
authors.initials: AP
authors.lastname: Larsen
authors.affiliation: Department of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege , Avenue de l'Hôpital, 1, B36, B-4000 Liège, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Francotte
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken, 2, DK-2100 Copenhagen, Denmark.
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken, 2, DK-2100 Copenhagen, Denmark.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tapken
authors.affiliation: Department of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege , Avenue de l'Hôpital, 1, B36, B-4000 Liège, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Goffin
authors.affiliation: Department of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege , Avenue de l'Hôpital, 1, B36, B-4000 Liège, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fraikin
authors.affiliation: Institut de Recherches Servier , Chemin de Ronde, 125, F-78290 Croissy-sur-Seine, France.
authors.forename: Daniel-Henri
authors.initials: DH
authors.lastname: Caignard
authors.affiliation: Institut de Recherches Servier , Chemin de Ronde, 125, F-78290 Croissy-sur-Seine, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lestage
authors.affiliation: Institut de Recherches Servier , Chemin de Ronde, 125, F-78290 Croissy-sur-Seine, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Danober
authors.affiliation: Department of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege , Avenue de l'Hôpital, 1, B36, B-4000 Liège, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken, 2, DK-2100 Copenhagen, Denmark.
authors.forename: Jette Sandholm
authors.initials: JS
authors.lastname: Kastrup
mesh_terms: D000818:Animals; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004594:Electrophysiology; D009865:Oocytes; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D058468:Receptors, Ionotropic Glutamate / Q000378:metabolism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D001581:Benzothiadiazines; D018091:Receptors, AMPA; D058468:Receptors, Ionotropic Glutamate
keywords: 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptor; Positive allosteric modulators; crystal structure; ligand-binding domain; structure−activity relationship; synthesis