Development of a Dihydroquinoline-Pyrazoline GluN2C/2D-Selective Negative Allosteric Modulator of the N-Methyl-d-aspartate Receptor

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dc.contributor.authorD'Erasmo, Michael P.en
dc.contributor.authorAkins, Nicholas S.en
dc.contributor.authorMa, Peipeien
dc.contributor.authorJing, Yaoen
dc.contributor.authorSwanger, Sharon A.en
dc.contributor.authorSharma, Savita K.en
dc.contributor.authorBartsch, Perry W.en
dc.contributor.authorMenaldino, David S.en
dc.contributor.authorArcoria, Paul J.en
dc.contributor.authorBui, Thi-Thienen
dc.contributor.authorPons-Bennaceur, Alexandreen
dc.contributor.authorLe, Phuongen
dc.contributor.authorAllen, James P.en
dc.contributor.authorUllman, Elijah Z.en
dc.contributor.authorNocilla, Kelsey A.en
dc.contributor.authorZhang, Jingen
dc.contributor.authorPerszyk, Riley E.en
dc.contributor.authorKim, Sukhanen
dc.contributor.authorAcker, Timothy M.en
dc.contributor.authorTaz, Azmainen
dc.contributor.authorBurton, Samantha L.en
dc.contributor.authorCoe, Kevinen
dc.contributor.authorFritzemeier, Russell G.en
dc.contributor.authorBurnashev, Nailen
dc.contributor.authorYuan, Hongjieen
dc.contributor.authorLiotta, Dennis C.en
dc.contributor.authorTraynelis, Stephen F.en
dc.date.accessioned2023-11-17T13:33:16Zen
dc.date.available2023-11-17T13:33:16Zen
dc.date.issued2023-08-11en
dc.date.updated2023-11-17T00:37:39Zen
dc.description.abstractSubunit-selective inhibition of N-methyl-d-aspartate receptors (NMDARs) is a promising therapeutic strategy for several neurological disorders, including epilepsy, Alzheimer’s and Parkinson’s disease, depression, and acute brain injury. We previously described the dihydroquinoline-pyrazoline (DQP) analogue 2a (DQP-26) as a potent NMDAR negative allosteric modulator with selectivity for GluN2C/D over GluN2A/B. However, moderate (<100-fold) subunit selectivity, inadequate cell-membrane permeability, and poor brain penetration complicated the use of 2a as an in vivo probe. In an effort to improve selectivity and the pharmacokinetic profile of the series, we performed additional structure-activity relationship studies of the succinate side chain and investigated the use of prodrugs to mask the pendant carboxylic acid. These efforts led to discovery of the analogue (S)-(−)-2i, also referred to as (S)-(−)-DQP-997-74, which exhibits >100- and >300-fold selectivity for GluN2C- and GluN2D-containing NMDARs (IC50 0.069 and 0.035 μM, respectively) compared to GluN2A- and GluN2B-containing receptors (IC50 5.2 and 16 μM, respectively) and has no effects on AMPA, kainate, or GluN1/GluN3 receptors. Compound (S)-(−)-2i is 5-fold more potent than (S)-2a. In addition, compound 2i shows a time-dependent enhancement of inhibitory actions at GluN2C- and GluN2D-containing NMDARs in the presence of the agonist glutamate, which could attenuate hypersynchronous activity driven by high-frequency excitatory synaptic transmission. Consistent with this finding, compound 2i significantly reduced the number of epileptic events in a murine model of tuberous sclerosis complex (TSC)-induced epilepsy that is associated with upregulation of the GluN2C subunit. Thus, 2i represents a robust tool for the GluN2C/D target validation. Esterification of the succinate carboxylate improved brain penetration, suggesting a strategy for therapeutic development of this series for NMDAR-associated neurological conditions.en
dc.description.versionPublished versionen
dc.format.extentPages 3059-3076en
dc.format.extent18 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1021/acschemneuro.3c00181en
dc.identifier.eissn1948-7193en
dc.identifier.issn1948-7193en
dc.identifier.issue17en
dc.identifier.orcidSwanger, Sharon [0000-0003-0615-6244]en
dc.identifier.pmid37566734en
dc.identifier.urihttp://hdl.handle.net/10919/116672en
dc.identifier.volume14en
dc.language.isoenen
dc.publisherAmerican Chemical Societyen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/37566734en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectNR2Cen
dc.subjectNR2Den
dc.subjectblood-brain barrieren
dc.subjecttuberous sclerosis complexen
dc.subjectseizureen
dc.subjectepilepsyen
dc.subjectNMDA RECEPTORen
dc.subjectNONCOMPETITIVE INHIBITIONen
dc.subjectGLUN2A-CONTAINING NMDARSen
dc.subjectSTRUCTURAL DETERMINANTSen
dc.subjectMESSENGER-RNASen
dc.subjectANTAGONISTSen
dc.subjectEXPRESSIONen
dc.subjectMECHANISMen
dc.subjectBINDINGen
dc.subjectGLUN1en
dc.subjectblood–brain barrieren
dc.subject3404 Medicinal and Biomolecular Chemistryen
dc.subject34 Chemical Sciencesen
dc.subjectBrain Disordersen
dc.subjectNeurodegenerativeen
dc.subject2.1 Biological and endogenous factorsen
dc.subject5 Development of treatments and therapeutic interventionsen
dc.subject2 Aetiologyen
dc.subject5.1 Pharmaceuticalsen
dc.subjectNeurologicalen
dc.subject3101 Biochemistry and cell biologyen
dc.subject3401 Analytical chemistryen
dc.subject.meshBrainen
dc.subject.meshAnimalsen
dc.subject.meshMiceen
dc.subject.meshGlutamic Aciden
dc.subject.meshReceptors, N-Methyl-D-Aspartateen
dc.subject.meshSynaptic Transmissionen
dc.subject.meshStructure-Activity Relationshipen
dc.titleDevelopment of a Dihydroquinoline-Pyrazoline GluN2C/2D-Selective Negative Allosteric Modulator of the <i>N</i>-Methyl-d-aspartate Receptoren
dc.title.serialACS Chemical Neuroscienceen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Veterinary Medicineen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicineen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiology/Otheren
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/Internal Medicineen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/Internal Medicine/Secondary Appointment- Internal Medicineen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/Internal Medicine/Internal Med-Subgroupen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Biomedical Research Institute at VTCen

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