title: Mechanism and site of inhibition of AMPA receptors: pairing a thiadiazole with a 2,3-benzodiazepine scaffold.
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.
authors: Department of Chemistry, and Center for Neuroscience Research, University at Albany, SUNY , Albany, New York 12222, United States.
authors: Congzhou
authors: C
authors: Wang
authors: Yan
authors: Y
authors: Han
authors: Andrew
authors: A
authors: Wu
authors: Sándor
authors: S
authors: Sólyom
authors: Li
authors: L
authors: Niu
mesh_terms: D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D057809:HEK293 Cells; D006801:Humans; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D018091:Receptors, AMPA; D013830:Thiadiazoles; C061950:GYKI 52466; D001569:Benzodiazepines