Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Design, synthesis, and structure-activity relationship of a novel series of GluN2C-selective potentiators.

ABSTRACT: NMDA receptors are tetrameric complexes composed of GluN1 and GluN2A-D subunits that mediate a slow Ca(2+)-permeable component of excitatory synaptic transmission. NMDA receptors have been implicated in a wide range of neurological diseases and thus represent an important therapeutic target. We herein describe a novel series of pyrrolidinones that selectively potentiate only NMDA receptors that contain the GluN2C subunit. The most active analogues tested were over 100-fold selective for recombinant GluN2C-containing receptors over GluN2A/B/D-containing NMDA receptors as well as AMPA and kainate receptors. This series represents the first class of allosteric potentiators that are selective for diheteromeric GluN2C-containing NMDA receptors.

SUBMITTER: Zimmerman SS

PROVIDER: S-EPMC3983368 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Design, synthesis, and structure-activity relationship of a novel series of GluN2C-selective potentiators.

Zimmerman Sommer S SS Khatri Alpa A Garnier-Amblard Ethel C EC Mullasseril Praseeda P Kurtkaya Natalie L NL Gyoneva Stefka S Hansen Kasper B KB Traynelis Stephen F SF Liotta Dennis C DC

Journal of medicinal chemistry 20140225 6

NMDA receptors are tetrameric complexes composed of GluN1 and GluN2A-D subunits that mediate a slow Ca(2+)-permeable component of excitatory synaptic transmission. NMDA receptors have been implicated in a wide range of neurological diseases and thus represent an important therapeutic target. We herein describe a novel series of pyrrolidinones that selectively potentiate only NMDA receptors that contain the GluN2C subunit. The most active analogues tested were over 100-fold selective for recombin ...[more]

PMID: 24512267

Similar Datasets

Synthesis and structure activity relationship of tetrahydroisoquinoline-based potentiators of GluN2C and GluN2D containing N-methyl-D-aspartate receptors.

Project description:We describe here the synthesis and evaluation of a series of tetrahydroisoquinolines that show subunit-selective potentiation of NMDA receptors containing the GluN2C or GluN2D subunits. Bischler-Napieralski conditions were employed in the key step for the conversion of acyclic amides to the corresponding tetrahydroisoquinoline-containing analogs. Compounds were evaluated using both two-electrode voltage clamp recordings from Xenopus laevis oocytes and imaging of mammalian BHK cells loaded with Ca(2+)-sensitive dyes. The most potent analogues had EC50 values of 300 nM and showed over 2-fold potentiation of the response to maximally effective concentrations of glutamate and glycine but had no effect on responses from NMDA receptors containing the GluN2A or GluN2B subunits AMPA, kainate, and GABA or glycine receptors or a variety of other potential targets. These compounds represent a potent class of small molecule subunit-selective potentiators of NMDA receptors.

| S-EPMC4850841 | biostudies-literature

Total synthesis and structure-activity relationship studies of a series of selective G protein inhibitors.

Project description:G proteins are key mediators of G protein-coupled receptor signalling, which facilitates a plethora of important physiological processes. The cyclic depsipeptides YM-254890 and FR900359 are the only known specific inhibitors of the Gq subfamily of G proteins; however, no synthetic route has been reported previously for these complex natural products and they are not easily isolated from natural sources. Here we report the first total synthesis of YM-254890 and FR900359, as well as of two known analogues, YM-385780 and YM-385781. The versatility of the synthetic approach also enabled the design and synthesis of ten analogues, which provided the first structure-activity relationship study for this class of compounds. Pharmacological characterization of all the compounds at Gq-, Gi- and Gs-mediated signalling provided succinct information on the structural requirements for inhibition, and demonstrated that both YM-254890 and FR900359 are highly potent inhibitors of Gq signalling, with FR900359 being the most potent. These natural products and their analogues represent unique tools for explorative studies of G protein inhibition.

| S-EPMC5559716 | biostudies-literature

Synthesis, Design, and Structure⁻Activity Relationship of the Pyrimidone Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase.

Project description:The inhibition of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) potentially represents a new treatment option for malaria, as P. falciparum relies entirely on a de novo pyrimidine biosynthetic pathway for survival. Herein, we report a series of pyrimidone derivatives as novel inhibitors of PfDHODH. The most potent compound, 26, showed high inhibition activity against PfDHODH (IC50 = 23 nM), with >400-fold species selectivity over human dihydroorotate dehydrogenase (hDHODH). The brand-new inhibitor scaffold targeting PfDHODH reported in this work may lead to the discovery of new antimalarial agents.

| S-EPMC6099574 | biostudies-literature

New carboxamide derivatives bearing benzenesulphonamide as a selective COX-II inhibitor: Design, synthesis and structure-activity relationship.

Project description:Sixteen new carboxamide derivatives bearing substituted benzenesulphonamide moiety (7a-p) were synthesized by boric acid mediated amidation of appropriate benzenesulphonamide with 2-amino-4-picoline and tested for anti-inflammatory activity. One compound 7c showed more potent anti-inflammatory activity than celecoxib at 3 h in carrageenan-induced rat paw edema bioassay. Compounds 7g and 7k also showed good anti-inflammatory activity comparable to celecoxib. Compound 7c appeared selectivity index (COX-2/COX-1) better than celecoxib. Compound 7k appeared selectivity index (COX-2/COX-1) a little higher than the half of celecoxib while compound 7g is non-selective for COX-2. The LD50 of compounds 7c, 7g and 7k were comparable to celecoxib.

| S-EPMC5602572 | biostudies-literature

Design, synthesis, and structure-activity relationship, molecular modeling, and NMR studies of a series of phenyl alkyl ketones as highly potent and selective phosphodiesterase-4 inhibitors.

Project description:Phosphodiesterase 4 catalyzes the hydrolysis of cyclic AMP and is a target for the development of anti-inflammatory agents. We have designed and synthesized a series of phenyl alkyl ketones as PDE4 inhibitors. Among them, 13 compounds were identified as having submicromolar IC(50) values. The most potent compounds have IC(50) values of in the mid- to low-nanomolar range. Compound 5v also showed preference for PDE4 with selectivity of >2000-fold over PDE7, PDE9, PDE2, and PDE5. Docking of 5v, 5zf, and 5za into the binding pocket of the PDE4 catalytic domain revealed a similar binding profile to PDE4 with rolipram except that the fluorine atoms of the difluoromethyl groups of 5v, 5za, and 5zf are within a reasonable range for hydrogen bond formation with the amide hydrogen of Thr 333 and the long alkyl chain bears additional van der Waals interactions with His 160, Asp 318, and Tyr 159.

| S-EPMC2950628 | biostudies-literature

Design, synthesis and structure-activity relationship of functionalized tetrahydro-?-carboline derivatives as novel PDE5 inhibitors.

Project description:Starting from tadalafil as a template, a series of functionalized tetrahydro-?-carboline derivatives have been prepared and identified as novel potent and selective PDE5 inhibitors. Replacing the 3,4-methylenedioxyphenyl at position 6 of tadalafil, together with elongation of the N2-methyl substituent and manipulation of the stereochemical aspects of the two chiral carbons led to the identification of compound XXI, a highly potent PDE5 inhibitor (IC(50) ?=?3 nM). Compound XXI was also highly selective for PDE5 versus PDE3B, PDE4B, and PDE11A, with a selectivity index of 52 and 235 towards PDE5 rather than PDE11 with both cAMP and cGMP as substrate, respectively.

| S-EPMC4980839 | biostudies-literature

Design, Synthesis and Structure-Activity Relationship Studies of Meridianin Derivatives as Novel JAK/STAT3 Signaling Inhibitors.

Project description:Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling is an attractive therapeutic target for tumor therapy. Herein, forty-eight novel meridianin derivatives were designed and synthesized, and their antitumor activity was evaluated in vitro both for activity optimization and structure-activity relationship (SAR) study. The results indicated that most derivatives exhibited significantly improved antitumor activity, especially for compound 6e. The compound 6e contains an isothiouronium linked by an alkyl chain consisting of six carbon atoms with IC50 ranging from 1.11 to 2.80 μM on various cancer cell lines. Consistently, the 6e dose dependently induced the apoptosis of A549 and DU145 cells, in which STAT3 is constitutively active. Western blotting assays indicated that the phosphorylation levels of JAK1, JAK2 and STAT3 were inhibited by 6e at 5 μM without significant change in the total STAT3 level. Moreover, 6e also suppressed the expression of STAT3 downstream genes, including c-Myc, Cyclin D1 and Bcl-XL at 10 μM. An additional in vivo study revealed that 6e at the dose of 10 mg/kg could potently inhibit the DU145 xenograft tumor without obvious body weight loss. These results clearly indicate that 6e could be a potential antitumor agent by targeting the JAK/STAT3 signaling pathway.

| S-EPMC8875316 | biostudies-literature

Design, Synthesis and Structure-Activity Relationship Studies of Novel Survivin Inhibitors with Potent Anti-Proliferative Properties.

Project description:The anti-apoptotic protein survivin is highly expressed in most human cancer cells, but has very low expression in normal differentiated cells. Thus survivin is considered as an attractive cancer drug target. Herein we report the design and synthesis of a series of novel survivin inhibitors based on the oxyquinoline scaffold from our recently identified hit compound UC-112. These new analogs were tested against a panel of cancer cell lines including one with multidrug-resistant phenotype. Eight of these new UC-112 analogs showed IC50 values in the nanomole range in anti-proliferative assays. The best three compounds among them along with UC-112 were submitted for NCI-60 cancer cell line screening. The results indicated that structural modification from UC-112 to our best compound 4g has improved activity by four folds (2.2 μM for UC-112 vs. 0.5 μM for 4g, average GI50 values over all cancer cell lines in the NCI-60 panel).Western blot analyses demonstrated the new compounds maintained high selectivity for survivin inhibition over other members in the inhibition of apoptosis protein family. When tested in an A375 human melanoma xenograft model, the most active compound 4g effectively suppressed tumor growth and strongly induced cancer cell apoptosis in tumor tissues. This novel scaffold is promising for the development of selective survivin inhibitors as potential anticancer agents.

| S-EPMC4466525 | biostudies-literature

Design, Synthesis, and Structure-Activity Relationship Study of Potent MAPK11 Inhibitors.

Project description:Huntington's disease (HD) is a rare single-gene neurodegenerative disease, which can only be treated symptomatically. Currently, there are no approved drugs for HD on the market. Studies have found that MAPK11 can serve as a potential therapeutic target for HD. Regrettably, no MAPK11 small molecule inhibitors have been approved at present. This paper presents three series of compounds that were designed and synthesized based on the structure of skepinone-L, a known MAPK14 inhibitor. Among the synthesized compounds, 13a and 13b, with IC50 values of 6.40 nM and 4.20 nM, respectively, displayed the best inhibitory activities against MAPK11. Furthermore, the structure-activity relationship (SAR) is discussed in detail, which is constructive in optimizing the MAPK11 inhibitors for better activity and effect against HD.

| S-EPMC8746797 | biostudies-literature

Design and Synthesis of New Anthranyl Phenylhydrazides: Antileishmanial Activity and Structure-Activity Relationship.

Project description:Leishmaniasis is a neglected tropical disease affecting millions of people worldwide. A centenary approach to antimonial-based drugs was first initiated with the synthesis of urea stibamine by Upendranath Brahmachari in 1922. The need for new drug development led to resistance toward antimoniates. New drug development to treat leishmaniasis is urgently needed. In this way, searching for new substances with antileishmanial activity, we synthesized ten anthranyl phenylhydrazide and three quinazolinone derivatives and evaluated them against promastigotes and the intracellular amastigotes of Leishmania amazonensis. Three compounds showed good activity against promastigotes 1b, 1d, and 1g, with IC50 between 1 and 5 μM. These new phenylhydrazides were tested against Leishmania arginase, but they all failed to inhibit this parasite enzyme, as we have shown in a previous study. To explain the possible mechanism of action, we proposed the enzyme PTR1 as a new target for these compounds based on in silico analysis. In conclusion, the new anthranyl hydrazide derivatives can be a promising scaffold for developing new substances against the protozoa parasite.

| S-EPMC10458276 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data