Dysfunction of excitatory amino acid transporters (EAATs) has been implicated in the pathogenesis of various neurological disorders, such as stroke, brain trauma, epilepsyand neurodegenerative diseases among others. EAAT2 is the main subtype responsible for glutamate clearance in the brain, having a key role in regulating transmission and preventing excitotoxicity. Therefore, compounds that increase the expression or activity of EAAT2 have therapeutic potential for neuroprotection. Previous studies identified molecular determinants for EAAT2 transport stimulation in a structural domain that lies at the interface of the rigid trimerization domain and the central substrate binding transport domain. In this work, a hybrid structure based approach was applied, based on this molecular domain, to create a high-resolution pharmacophore. Subsequently, a virtual screening of a library of small molecules was performed; identifying ten hit molecules that interact at the proposed domain. Among these, three compounds were determined to be activators, four were inhibitors and three had no effect on EAAT2-mediated transport in vitro. Further characterization of the two best ranking EAAT2 activators for efficacy, potency and selectivity for glutamate over monoamine transporters subtypes and NMDA receptors, and efficacy in cultured astrocytes is demonstrated. Mutagenesis studies suggest that the EAAT2 activators interact with residues forming the interface between the trimerization and the transport domains. These compounds enhance the glutamate translocation rate, with no effect on substrate interaction, suggesting an allosteric mechanism. The identification of these novel positive allosteric modulators of EAAT2 offer an innovative approach for the development of therapies based on glutamate transport enhancement.
Pharmacology, Toxicology and Pharmaceutical Science
14
14%
Neuroscience
12
12%
Medicine and Dentistry
8
8%
Chemistry
8
8%
Other
9
9%
Unknown
28
29%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 7. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 05 July 2022.
All research outputs
#6,130,449
of 31,634,113 outputs
Outputs from ACS Chemical Neuroscience
#1,146
of 3,209 outputs
Outputs of similar age
#82,379
of 356,137 outputs
Outputs of similar age from ACS Chemical Neuroscience
#17
of 59 outputs
Altmetric has tracked 31,634,113 research outputs across all sources so far. Compared to these this one has done well and is in the 79th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 3,209 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 11.1. This one has gotten more attention than average, scoring higher than 52% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 356,137 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 75% of its contemporaries.
We're also able to compare this research output to 59 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 69% of its contemporaries.
