ArticleACS chemical neuroscience2014
Mechanism and site of inhibition of AMPA receptors: pairing a thiadiazole with a 2,3-benzodiazepine scaffold.
Article in ACS chemical neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 29 citations in OpenAlex.
- Allosteric competition and inhibition in AMPA receptors.Nature structural & molecular biology · 2024Article
- Allosteric Competition and Inhibition in AMPA Receptors.bioRxiv : the preprint server for biology · 2023Article
- RNA aptamers for AMPA receptors.Neuropharmacology · 2021Review
- Phthalazine-1,4-dione derivatives as non-competitive AMPA receptor antagonists: design, synthesis, anticonvulsant evaluation, ADMET profile and molecular docking.Molecular diversity · 2019Article
- Noncompetitive antagonists induce cooperative AMPA receptor channel gating.The Journal of general physiology · 2019Article
- Structural Bases of Noncompetitive Inhibition of AMPA-Subtype Ionotropic Glutamate Receptors by Antiepileptic Drugs.Neuron · 2016Article
- Mechanism-based design of 2,3-benzodiazepine inhibitors for AMPA receptors.Acta pharmaceutica Sinica. B · 2015Review
- Mechanism of inhibition of the GluA1 AMPA receptor channel opening by the 2,3-benzodiazepine compound GYKI 52466 and a N-methyl-carbamoyl derivative.Biochemistry · 2014Article
- Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
2,3-Benzodiazepine compounds are synthesized as drug candidates for treatment of various neurological disorders involving excessive activity of AMPA receptors. Here we report that pairing a thiadiazole moiety with a 2,3-benzodiazepine scaffold via the N-3 position yields an inhibitor type with >28-fold better potency and selectivity on AMPA receptors than the 2,3-benzodiazepine scaffold alone. Using whole-cell recording, we characterized two thiadiazolyl compounds, that is, one contains a 1,3,4-thiadiazole moiety and the other contains a 1,2,4-thiadiazole-3-one moiety. These compounds exhibit potent, equal inhibition of both the closed-channel and the open-channel conformations of all four homomeric AMPA receptor channels and two GluA2R-containing complex AMPA receptor channels. Furthermore, these compounds bind to the same receptor site as GYKI 52466 does, a site we previously termed as the "M" site. A thiadiazole moiety is thought to occupy more fully the side pocket of the receptor site or the "M" site, thereby generating a stronger, multivalent interaction between the inhibitor and the receptor binding site. We suggest that, as a heterocycle, a thiadiazole can be further modified chemically to produce a new class of even more potent, noncompetitive inhibitors of AMPA receptors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.