CMPDA

CMPDA is a positive allosteric modulator of AMPA receptors with EC50s of 45.4 ± 4.2 nM/63.4 ± 5.6 nM for GluA2i/GluA2o receptor. IC50 value: 45.4 ± 4.2 nM/63.4 ± 5.6 nM(GluA2i/GluA2o) [1] Target: AMPAR modulator CMPDA was nearly equipotent at modulating the two isoforms of GluA2 receptors, whereas CMPDB displayed a modest preference for the flip splice variant. Similar to CX614, CMPDA slowed the rate of deactivation of GluA2o receptors approximately 2-fold but had no effect on GluA2i receptor deactivation [1].

References:
[1]. Timm DE, et al. Structural and functional analysis of two new positive allosteric modulators of GluA2 desensitization and deactivation. Mol Pharmacol. 2011 Aug;80(2):267-80.

Targeting IkappaB Kinase beta/NF-kappaB Signaling in Human Prostate Cancer by a Novel IkappaB Kinase beta Inhibitor CmpdA.[Pubmed:27196761]

Mol Cancer Ther. 2016 Jul;15(7):1504-14.

NF-kappaB plays an important role in many types of cancer, including prostate cancer, but the role of the upstream kinase of NF-kappaB, IKKbeta, in prostate cancer has neither been fully documented nor are there any effective IKKbeta inhibitors used in clinical settings. Here, we have shown that IKKbeta activity is mediated by multiple kinases including IKKalpha in human prostate cancer cell lines that express activated IKKbeta. IHC analysis (IHC) of human prostate cancer tissue microarrays (TMA) demonstrates that phosphorylation of IKKalpha/beta within its activation loop gradually increases in low to higher stage tumors as compared with normal tissue. The expression of cell proliferation and survival markers (Ki-67, Survivin) and epithelial-to-mesenchymal transition (EMT) markers (Slug, Snail), as well as cancer stem cell (CSC)-related transcription factors (Nanog, Sox2, Oct-4), also increase in parallel among the respective TMA samples analyzed. IKKbeta, but not NF-kappaB, is found to regulate Nanog, which, in turn, modulates the levels of Oct4, Sox2, Snail, and Slug, indicating an essential role of IKKbeta in regulating CSCs and EMT. The novel IKKbeta inhibitor CMPDA inhibits constitutively activated IKKbeta/NF-kappaB signaling, leading to induction of apoptosis and inhibition of proliferation, migration, and stemness in these cells. CMPDA also significantly inhibits tumor growth in xenografts without causing apparent in vivo toxicity. Furthermore, CMPDA and docetaxel act synergistically to inhibit proliferation of prostate cancer cells. These results indicate that IKKbeta plays a pivotal role in prostate cancer, and targeting IKKbeta, including in combination with docetaxel, may be a potentially useful strategy for treating advanced prostate cancer. Mol Cancer Ther; 15(7); 1504-14. (c)2016 AACR.

Structural and functional analysis of two new positive allosteric modulators of GluA2 desensitization and deactivation.[Pubmed:21543522]

Mol Pharmacol. 2011 Aug;80(2):267-80.

At the dimer interface of the extracellular ligand-binding domain of alpha-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.

CMPDA is a positive allosteric modulator of AMPA receptors with EC50s of 45.4 ± 4.2 nM/63.4 ± 5.6 nM for GluA2i/GluA2o receptor.

CMPDA,380607-77-2,Natural Products,AMPAR, buy CMPDA , CMPDA supplier , purchase CMPDA , CMPDA cost , CMPDA manufacturer , order CMPDA , high purity CMPDA