title: A novel class of negative allosteric modulators of NMDA receptor function.
abstract: NMDA receptors mediate a slow Ca(2+)-permeable component of excitatory synaptic transmission, and are involved in numerous normal brain functions including learning and memory. NMDA receptor over-activation can lead to cell death and abnormal excitation in ischemia associated with stroke, traumatic brain injury, and epilepsy. We have explored a series of novel noncompetitive allosteric modulators of NMDA receptor function characterized by an iminothiazolidinone ring. Saturating concentrations of these compounds inhibit NMDA receptors to varying maximal extents, raising the possibility that they may attenuate over-activation in pathological situations while preserving some minimal receptor function, which may limit side-effects. The best in class compounds have sub-micromolar IC50 values and show modest preference for GluN2C- and GluN2D-containing receptors.
authors.affiliation: Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, GA 30322, United States.
authors.forename: Brooke M
authors.initials: BM
authors.lastname: Katzman
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, United States.
authors.forename: Riley E
authors.initials: RE
authors.lastname: Perszyk
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, United States.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, GA 30322, United States.
authors.forename: Yesim Altas
authors.initials: YA
authors.lastname: Tahirovic
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, United States.
authors.forename: Ayodeji E
authors.initials: AE
authors.lastname: Sotimehin
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, United States.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
authors.affiliation: Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, GA 30322, United States. Electronic address: dliotta@emory.edu.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
mesh_terms: D000494:Allosteric Regulation; D020128:Inhibitory Concentration 50; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects*; D012995:Solubility; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D053778:Thiazolidines
keywords: GluN2; Glutamate; N-Methyl-d-aspartate; Neuroprotection; Noncompetitive antagonist