Ring-Fused Thiadiazines as Core Structures for the Development of Potent AMPA Receptor Potentiators

Pirotte, Bernard; Francotte, Pierre; Goffin, Eric; Fraikin, Pierre; Danober, Laurence; Lesur, Brigitte; Botez, Iuliana; Caignard, Daniel‐Henri; Lestage, Pierre; Tullio, Pascal De

doi:10.2174/092986710792927859

Cited by 21 publications

(19 citation statements)

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“…In parallel with these electrophysiological studies, AMPAR PAMs were soon shown to enhance learning and memory (Staubli et al, 1994a). Since then, many other structural classes have been described (Ward and Harries, 2010; Pirotte et al, 2010) and their positive effects on cognition in laboratory animals and human patients have been extensively reported and reviewed (Morrow et al, 2006; Arai and Kessler, 2007; O'Neill and Dix, 2007; Cleva et al, 2010; Lynch et al, 2011). The potential site of action of AMPAR PAMs, together with other cognitive enhancing agents that may act at the glutamatergic synapse, is shown schematically in Fig.…”

Section: Indirect Modulationmentioning

confidence: 99%

The NMDA receptor as a target for cognitive enhancement

Collingridge

Volianskis²,

Bannister³

et al. 2013

Neuropharmacology

207

157

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NMDA receptors (NMDAR) play an important role in neural plasticity including long-term potentiation and long-term depression, which are likely to explain their importance for learning and memory. Cognitive decline is a major problem facing an ageing human population, so much so that its reversal has become an important goal for scientific research and pharmaceutical development. Enhancement of NMDAR function is a core strategy toward this goal. In this review we indicate some of the major ways of potentiating NMDAR function by both direct and indirect modulation. There is good evidence that both positive and negative modulation can enhance function suggesting that a subtle approach correcting imbalances in particular clinical situations will be required. Excessive activation and the resultant deleterious effects will need to be carefully avoided. Finally we describe some novel positive allosteric modulators of NMDARs, with some subunit selectivity, and show initial evidence of their ability to affect NMDAR mediated events.

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Section: Indirect Modulationmentioning

confidence: 99%

The NMDA receptor as a target for cognitive enhancement

Collingridge

Volianskis²,

Bannister³

et al. 2013

Neuropharmacology

207

157

View full text Add to dashboard Cite

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“…Hence, a 4-5-fold lower binding affinity of the modulator is seen for the monomeric form of the GluA2 LBD than for the preformed dimeric LBD. As the pure enantiomer rapidly epimerizes in solution reforming the mixture of isomers [29], the equilibrium might be changed upon binding of the (S)-enantiomer of IDRA-21 to the protein and, hence, it might be plausible to consider IDRA-21 as one compound in our ITC experiments. However, the value of n does not seem to affect the determined values of H, S and K d .…”

Section: Binding Affinities Of Bpam-97 Towards Lbd-l483y-n754s and Lbmentioning

confidence: 99%

Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2

Krintel

Frydenvang

Olsen

et al. 2011

Biochemical Journal

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Positive allosteric modulators of the ionotropic glutamate receptor-2 (GluA2) are promising compounds for the treatment of cognitive disorders, e.g. Alzheimer's disease. These modulators bind within the dimer interface of the LBD (ligand-binding domain) and stabilize the agonist-bound conformation slowing receptor desensitization and/or deactivation. In the present study, we employ isothermal titration calorimetry to determine binding affinities and thermodynamic details of binding of modulators of GluA2. A mutant of the LBD of GluA2 (LBD-L483Y-N754S) that forms a stable dimer in solution was used. The potent GluA2 modulator BPAM-97 was used as a reference compound. Evidence that BPAM-97 binds in the same pocket as the well-known GluA2 modulator cyclothiazide was obtained from X-ray structures. The LBD-L483Y-N754S:BPAM-97 complex has a Kd of 5.6 μM (ΔH=-4.9 kcal/mol, -TΔS=-2.3 kcal/mol; where 1 kcal≈4.187 kJ). BPAM-97 was used in a displacement assay to determine a Kd of 0.46 mM (ΔH=-1.2 kcal/mol, -TΔS=-3.3 kcal/mol) for the LBD-L483Y-N754S:IDRA-21 complex. The major structural factors increasing the potency of BPAM-97 over IDRA-21 are the increased van der Waals contacts to, primarily, Met496 in GluA2 imposed by the ethyl substituent of BPAM-97. These results add important information on binding affinities and thermodynamic details, and provide a new tool in the development of drugs against cognitive disorders.

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“…Sulfonamides are important structural motifs with wide applications in pharmaceuticals, agrochemical, biological and medicinal studies . Among them, benzothiadiazine 1,1‐dioxides (benzosultams) and their analogues are found to very important heterocyclic scaffolds in drug discovery due to their promising bioactivities including hypoglycemic, selective antagonists of CXR2, AMPA receptors potentiators, antidepressant, Glut‐1 transporter inhibitors, and HCV polymerase inhibitors (Figure ). Specifically, 2‐aminobenzenesulfonamides act as a key precursor for the synthesis of benzothiadiazine 1,1‐dioxides .…”

Section: Introductionmentioning

confidence: 99%

Iridium‐Catalyzed ortho‐C−H Amidation of Benzenesulfonamides with Sulfonyl Azides

et al. 2019

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We developed herein an iridium-catalyzed direct CÀ H activation/ CÀ N bond formation reaction of benzenesulfonamides with sulfonyl azides. The amidation reaction provides a protocol for the synthesis of 2-aminobenzesulfonamides in good to excellent yields. This strategy features a wide substrate scope, tolerates a broad range of functional groups under external oxidant-free conditions and only releases molecular nitrogen as the sole by-product. Moreover, the preliminary mechanism was investigated and the proposed reaction pathway was provided. Figure 1. Selected biologically active benzothidiazine-1,1-dioxides containing the 2-aminobenzenesulfonamides motif.

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Ring-Fused Thiadiazines as Core Structures for the Development of Potent AMPA Receptor Potentiators

Cited by 21 publications

References 0 publications

The NMDA receptor as a target for cognitive enhancement

The NMDA receptor as a target for cognitive enhancement

Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2

Iridium‐Catalyzed ortho‐C−H Amidation of Benzenesulfonamides with Sulfonyl Azides

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