Abstract
At the dimer interface of the extracellular ligand-binding domain of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors a hydrophilic pocket is formed that is known to interact with two classes of positive allosteric modulators, represented by cyclothiazide and the ampakine 2H,3H,6aH-pyrrolidino(2,1–3′,2′)1,3-oxazino(6′,5′-5,4)benzo(e)1,4-dioxan-10-one (CX614). Here, we present structural and functional data on two new positive allosteric modulators of AMPA receptors, phenyl-1,4-bis-alkylsulfonamide (CMPDA) and phenyl-1,4-bis-carboxythiophene (CMPDB). Crystallographic data show that these compounds bind within the modulator-binding pocket and that substituents of each compound overlap with distinct moieties of cyclothiazide and CX614. The goals of the present study were to determine 1) the degree of modulation by CMPDA and CMPDB of AMPA receptor deactivation and desensitization; 2) whether these compounds are splice isoform-selective; and 3) whether predictions of mechanism of action could be inferred by comparing molecular interactions between the ligand-binding domain and each compound with those of cyclothiazide and CX614. CMPDB was found to be more isoform-selective than would be predicted from initial binding assays. It is noteworthy that these new compounds are both more potent and more effective and may be more clinically relevant than the AMPA receptor modulators described previously.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported by the National Institutes of Health National Institute of Mental Health [2R01-MH064700-06A2]; and the National Institutes of Health National Institute of Neurological Disorders and Stroke [S11-NS055883].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.070243.
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ABBREVIATIONS:
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
- CMPDA
- phenyl-1,4-bis-alkylsulfonamide
- CMPDB
- phenyl-1,4-bis-carboxythiophene
- Deact
- deactivation
- Des
- desensitization
- CTZ
- cyclothiazide
- CX614
- 2H,3H,6aH-pyrrolidino(2,1-3′,2′)1,3-oxazino(6′,5′-5,4)benzo(e)1,4-dioxan-10-one
- LBC
- (ligand-binding core)
- DMSO
- dimethyl sulfoxide
- WT
- wild type
- CC
- closed clamshell
- OC
- open clamshell
- i
- flip
- o
- flop
- HEK
- human embryonic kidney
- FLIPR
- fluorometric imaging plate reader
- BAPTA
- 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
- PEG
- polyethylene glycol
- LY404187
- N-[2-(4′-cyanobiphenyl-4-yl)propyl]propane-2-sulfonamide
- CX546
- 2,3-dihydro-1,4-benzodioxin-7-yl-(1-piperidyl)methanone
- CX516
- 6-(piperidin-1-ylcarbonyl)quinoxaline.
- Received November 30, 2010.
- Accepted May 4, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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