Distinct Structural Features of Cyclothiazide Are Responsible for Effects on Peak Current Amplitude and Desensitization Kinetics at iGluR2

Hald, Helle; Ahring, Philip K.; Timmermann, Daniel B.; Liljefors, Tommy; Gajhede, Michael; Kastrup, J.S.

doi:10.1016/j.jmb.2009.07.002

Cited by 28 publications

(47 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The dimer interface between agonist binding domains of AMPA receptor subunits is a well-described binding site for allosteric modulation (Sun et al, 2002; Jin et al, 2005; Hald et al, 2009; Ptak et al, 2009; Ahmed et al, 2010), and positive allosteric modulators of AMPA receptor function are currently being evaluated for the treatment of depression and attention-deficit hyperactivity disorder (ADHD), as well as for the improvement of cognitive deficits in Alzheimer’s disease (Ward et al, 2010). Allosteric AMPA receptor modulators enhance receptor function by reducing desensitization and/or by slowing deactivation of the receptor response.…”

Section: Discussionmentioning

confidence: 99%

Subunit-Selective Allosteric Inhibition of Glycine Binding to NMDA Receptors

Hansen¹,

Ogden²,

Traynelis³

2012

J. Neurosci.

102

117

View full text Add to dashboard Cite

NMDA receptors are ligand-gated ion channels that mediate excitatory neurotransmission in the brain, and are involved in numerous neuropathological conditions. NMDA receptors are activated upon simultaneous binding of co-agonists glycine and glutamate to the GluN1 and GluN2 subunits, respectively. Subunit-selective modulation of NMDA receptor function by ligand binding to modulatory sites distinct from the agonist binding sites could allow pharmacological intervention with therapeutically beneficial mechanisms. Here, we show the mechanism of action for TCN-201, a new GluN1/GluN2A-selective NMDA receptor antagonist whose inhibition can be surmounted by glycine. Electrophysiological recordings from chimeric and mutant rat NMDA receptors suggest that TCN-201 binds to a novel allosteric site located at the dimer interface between the GluN1 and GluN2 agonist binding domains. Furthermore, we demonstrate that occupancy of this site by TCN-201 inhibits NMDA receptor function by reducing glycine potency. TCN-201 is therefore a negative allosteric modulator of glycine binding.

show abstract

Section: Discussionmentioning

confidence: 99%

Subunit-Selective Allosteric Inhibition of Glycine Binding to NMDA Receptors

Hansen¹,

Ogden²,

Traynelis³

2012

J. Neurosci.

102

117

View full text Add to dashboard Cite

show abstract

“…This figure was generated with pdb files from the RCSB Protein Data Bank using the The PyMol Molecular Graphics System (version 1.3, Schrödinger, LLC). The following are shown in cartoon representation, aligned manually: Chains A and C of the 3H6T.pdb file for cyclothiazide (Hald et al, 2009), Chains D and F of the 2AL4.pdb file for CX614 (Jin et al, 2005), and Chain A of JAMI1001A (4FAT.pdb). A mask was applied to the CX614 subunit of 2AL4 so only one conformation of CX614 would be displayed.…”

Section: Figurementioning

confidence: 99%

Functional analysis of a novel positive allosteric modulator of AMPA receptors derived from a structure-based drug design strategy

et al. 2013

View full text Add to dashboard Cite

Positive allosteric modulators of α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) receptors facilitate synaptic plasticity and can improve various forms of learning and memory. These modulators show promise as therapeutic agents for the treatment of neurological disorders such as schizophrenia, ADHD, and mental depression. Three classes of positive modulator, the benzamides, the thiadiazides, and the biarylsulfonamides differentially occupy a solvent accessible binding pocket at the interface between the two subunits that form the AMPA receptor ligand-binding pocket. Here, we describe the electrophysiological properties of a new chemotype derived from a structure-based drug design strategy (SBDD), which makes similar receptor interactions compared to previously reported classes of modulator. This pyrazole amide derivative, JAMI1001A, with a promising developability profile, efficaciously modulates AMPA receptor deactivation and desensitization of both flip and flop receptor isoforms.

show abstract

“…Protein structures were visualized using The PyMol Molecular Graphics System (version 1.3, Schrödinger, LLC) in cartoon representation, using PDB files 2AL4 for CX614 (Jin et al, 2005); 3H6T for cyclothiazide (Hald et al, 2009); 3RN8 and 3RNN for CMPD A and B, respectively (Timm et al, 2011), obtained from the RCSB Protein Data Bank.…”

Section: Methodsmentioning

confidence: 99%

Functional insight into development of positive allosteric modulators of AMPA receptors

et al. 2014

View full text Add to dashboard Cite

Positive allosteric modulators of α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) ionotropic glutamate receptors facilitate synaptic plasticity and contribute essentially to learning and memory, properties which make AMPA receptors targets for drug discovery and development. One region at which several different classes of positive allosteric modulators bind lies at the dimer interface between the ligand-binding core of the second, membrane-proximal, extracellular domain of AMPA receptors. This solvent-accessible binding pocket has been the target of drug discovery efforts, leading to the recent delineation of five “subsites” which differentially allow access to modulator moieties, and for which distinct modulator affinities and apparent efficacies are attributed. Here we use the voltage-clamp technique in conjunction with rapid drug application to study the effects of mutants lining subsites “A” and “B” of the allosteric modulator pocket to assess affinity and efficacy of allosteric modulation by cyclothiazide, CX614, CMPDA and CMPDB. A novel analysis of the decay of current produced by the onset of desensitization has allowed us to estimate both affinity and efficacy from single concentrations of modulator. Such an approach may be useful for effective high throughput screening of new target compounds.

show abstract

Distinct Structural Features of Cyclothiazide Are Responsible for Effects on Peak Current Amplitude and Desensitization Kinetics at iGluR2

Cited by 28 publications

References 41 publications

Subunit-Selective Allosteric Inhibition of Glycine Binding to NMDA Receptors

Subunit-Selective Allosteric Inhibition of Glycine Binding to NMDA Receptors

Functional analysis of a novel positive allosteric modulator of AMPA receptors derived from a structure-based drug design strategy

Functional insight into development of positive allosteric modulators of AMPA receptors

Contact Info

Product

Resources

About