title: Structure-activity relationships and pharmacophore model of a noncompetitive pyrazoline containing class of GluN2C/GluN2D selective antagonists.
abstract: Here we describe the synthesis and structure-activity relationship for a class of pyrazoline-containing dihydroquinolone negative allosteric modulators of the NMDA receptor that show strong subunit selectivity for GluN2C- and GluN2D-containing receptors over GluN2A- and GluN2B-containing receptors. Several members of this class inhibit NMDA receptor responses in the nanomolar range and are more than 50-fold selective over GluN1/GluN2A and GluN1/GluN2B NMDA receptors, as well as AMPA, kainate, GABA, glycine, nicotinic, serotonin, and purinergic receptors. Analysis of the purified enantiomers of one of the more potent and selective compounds shows that the S-enantiomer is both more potent and more selective than the R-enantiomer. The S-enantiomer had an IC50 of 0.17-0.22 μM at GluN2D- and GluN2C-containing receptors, respectively, and showed over 70-fold selectivity over other NMDA receptor subunits. The subunit selectivity of this class of compounds should be useful in defining the role of GluN2C- and GluN2D-containing receptors in specific brain circuits in both physiological and pathophysiological conditions.
authors.affiliation: Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States. dliotta@emory.edu
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Acker
authors.forename: Alpa
authors.initials: A
authors.lastname: Khatri
authors.forename: Katie M
authors.initials: KM
authors.lastname: Vance
authors.forename: Cathryn
authors.initials: C
authors.lastname: Slabber
authors.forename: John
authors.initials: J
authors.lastname: Bacsa
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
mesh_terms: D001812:Blood-Brain Barrier; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011720:Pyrazoles / Q000737:chemistry*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D018691:Excitatory Amino Acid Antagonists; D011720:Pyrazoles; D016194:Receptors, N-Methyl-D-Aspartate
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