title: Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design.
abstract: The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate. NMDARs are critical to synaptic signaling and plasticity, and their dysfunction has been implicated in a number of neurological disorders, including schizophrenia, depression, and Alzheimer's disease. Herein we describe the discovery of potent GluN2A-selective NMDAR positive allosteric modulators (PAMs) starting from a high-throughput screening hit. Using structure-based design, we sought to increase potency at the GluN2A subtype, while improving selectivity against related α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The structure-activity relationship of channel deactivation kinetics was studied using a combination of electrophysiology and protein crystallography. Effective incorporation of these strategies resulted in the discovery of GNE-0723 (46), a highly potent and brain penetrant GluN2A-selective NMDAR PAM suitable for in vivo characterization.
authors.forename: Matthew
authors.initials: M
authors.lastname: Volgraf
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Sellers
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Wu
authors.forename: Cuong Q
authors.initials: CQ
authors.lastname: Ly
authors.forename: Elisia
authors.initials: E
authors.lastname: Villemure
authors.forename: Richard M
authors.initials: RM
authors.lastname: Pastor
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Po-wai
authors.initials: PW
authors.lastname: Yuen
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Lu
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Luo
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Mingcui
authors.initials: M
authors.lastname: Liu
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Sun
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Fu
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Lupardus
authors.forename: Heidi J A
authors.initials: HJ
authors.lastname: Wallweber
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.forename: Gauri
authors.initials: G
authors.lastname: Deshmukh
authors.forename: Emile
authors.initials: E
authors.lastname: Plise
authors.forename: Suzanne
authors.initials: S
authors.lastname: Tay
authors.forename: Paul
authors.initials: P
authors.lastname: Reynen
authors.forename: James
authors.initials: J
authors.lastname: Herrington
authors.forename: Amy
authors.initials: A
authors.lastname: Gustafson
authors.forename: Yichin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Ion Channels Group, Evotec AG ; Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
authors.forename: Akim
authors.initials: A
authors.lastname: Dirksen
authors.affiliation: Ion Channels Group, Evotec AG ; Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
authors.forename: Matthias G A
authors.initials: MG
authors.lastname: Dietz
authors.forename: Yanzhou
authors.initials: Y
authors.lastname: Liu
authors.forename: Tzu-Ming
authors.initials: TM
authors.lastname: Wang
authors.forename: Jesse E
authors.initials: JE
authors.lastname: Hanson
authors.forename: David
authors.initials: D
authors.lastname: Hackos
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D002118:Calcium; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate