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ABSTRACT Allosteric modulators of ion channels typically alter the transitions rates between conformational states without changing the properties of the open pore. Here we describe a new

class of positive allosteric modulators of _N_-methyl d-aspartate receptors (NMDARs) that mediate a calcium-permeable component of glutamatergic synaptic transmission and play essential

roles in learning, memory and cognition, as well as neurological disease. EU1622-14 increases agonist potency and channel-open probability, slows receptor deactivation and decreases both

single-channel conductance and calcium permeability. The unique functional selectivity of this chemical probe reveals a mechanism for enhancing NMDAR function while limiting excess calcium

influx, and shows that allosteric modulators can act as biased modulators of ion-channel permeation. Access through your institution Buy or subscribe This is a preview of subscription

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* Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS ALLOSTERIC COMPETITION AND INHIBITION IN AMPA RECEPTORS Article

Open access 04 June 2024 GLUN2A AND GLUN2B NMDA RECEPTORS USE DISTINCT ALLOSTERIC ROUTES Article Open access 05 August 2021 BI-DIRECTIONAL ALLOSTERIC PATHWAY IN NMDA RECEPTOR ACTIVATION AND

MODULATION Article Open access 13 October 2024 DATA AVAILABILITY The data that support the findings of this study are available from the corresponding author upon reasonable request. CODE

AVAILABILITY The code that support the analysis of the findings contained in this study are available from the corresponding author upon reasonable request. REFERENCES * Traynelis, S. F. et

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ACKNOWLEDGEMENTS The authors thank K. Ogden for help with analytical software development and Y. Du and the Emory Chemical Biology Discovery Center for their invaluable assistance. This work

was supported by the NINDS (NS065371 and NS111619, to S.F.T.), NICHD (HD082373, to H.Y.), NIMH (MH109026, to G.B.), Citizens United for Research in Epilepsy (to S.A.S.) and the Emory

University Research Committee (to S.A.S.). AUTHOR INFORMATION Author notes * Gabriela Fernandez-Cuervo Present address: Department of Pathology, Stanford University School of Medicine,

Stanford, CA, USA AUTHORS AND AFFILIATIONS * Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA Riley E. Perszyk, Sharon A. Swanger, Chris

Shelley, Alpa Khatri, Jing Zhang, Phuong Le, Hongjie Yuan & Stephen F. Traynelis * Virginia Tech Carilion Research Institute, Roanoke, VA, USA Sharon A. Swanger * Department of Internal

Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA, USA Sharon A. Swanger * Department of Biomedical Sciences and Pathobiology, Virginia-Maryland School of Veterinary

Medicine, Virginia Tech, Blacksburg, VA, USA Sharon A. Swanger * Department of Biology, University of the South, Sewanee, TN, USA Chris Shelley * Department of Chemistry, Emory University,

Atlanta, GA, USA Gabriela Fernandez-Cuervo, Matthew P. Epplin, Ethel Garnier-Amblard, Pavan Kumar Reddy Gangireddy, David S. Menaldino, Dennis C. Liotta & Lanny S. Liebeskind *

Department of Physiology, Emory University, Atlanta, GA, USA Pernille Bülow * Department of Cell Biology, Emory University, Atlanta, GA, USA Pernille Bülow & Gary J. Bassell Authors *

Riley E. Perszyk View author publications You can also search for this author inPubMed Google Scholar * Sharon A. Swanger View author publications You can also search for this author

inPubMed Google Scholar * Chris Shelley View author publications You can also search for this author inPubMed Google Scholar * Alpa Khatri View author publications You can also search for

this author inPubMed Google Scholar * Gabriela Fernandez-Cuervo View author publications You can also search for this author inPubMed Google Scholar * Matthew P. Epplin View author

publications You can also search for this author inPubMed Google Scholar * Jing Zhang View author publications You can also search for this author inPubMed Google Scholar * Phuong Le View

author publications You can also search for this author inPubMed Google Scholar * Pernille Bülow View author publications You can also search for this author inPubMed Google Scholar * Ethel

Garnier-Amblard View author publications You can also search for this author inPubMed Google Scholar * Pavan Kumar Reddy Gangireddy View author publications You can also search for this

author inPubMed Google Scholar * Gary J. Bassell View author publications You can also search for this author inPubMed Google Scholar * Hongjie Yuan View author publications You can also

search for this author inPubMed Google Scholar * David S. Menaldino View author publications You can also search for this author inPubMed Google Scholar * Dennis C. Liotta View author

publications You can also search for this author inPubMed Google Scholar * Lanny S. Liebeskind View author publications You can also search for this author inPubMed Google Scholar * Stephen

F. Traynelis View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS The authors contributed in the following manner: conceptualization (S.F.T.,

R.E.P. and S.A.S.); data curation and formal analysis (R.E.P., S.A.S., C.S., A.K., G.F.-C., H.Y. and S.F.T.); funding acquisition (S.A.S., S.F.T., H.Y., D.C.L. and G.J.B.); investigation

(R.E.P., S.A.S., C.S., A.K., J.Z., P.L., E.G.-A., G.F.-C., M.P.E., D.S.M. and P.B.); development or design of methodology (R.E.P., S.A.S., S.F.T., E.G.-A., G.F.-C., M.P.E., G.J.B., D.S.M.,

D.C.L. and L.S.L.); project administration (R.E.P., S.F.T. and S.A.S.); provision of reagents, materials and analysis tools (P.K.R.G., E.G.-A., G.F.-C., P.B., G.J.B., M.P.E., D.S.M., D.C.L.

and L.S.L.); software (R.E.P. and S.F.T.); supervision (S.F.T., L.S.L., D.C.L. and G.J.B.); verification (R.E.P., S.A.S., C.S., A.K., G.F.-C., M.P.E. and D.S.M.); and visualization and

writing (all authors). CORRESPONDING AUTHOR Correspondence to Stephen F. Traynelis. ETHICS DECLARATIONS COMPETING INTERESTS Several authors have competing interests. S.F.T. is a consultant

for Janssen Pharmaceuticals, principal investigator on research grants from Janssen and Allergan to Emory University School of Medicine, a member of the scientific advisory board for Sage

Therapeutics, the GRIN2B Foundation, and the CureGRIN Foundation, co-founder of NeurOp and receives royalties for software. D.C.L. is a member of the Board of Directors for NeurOp. D.C.L.,

D.S.M., E.G.A., G.F.C., P.K.R.G., L.S.L., M.P.E., S.F.T. are co-inventors on Emory-owned intellectual property that includes allosteric modulators of NMDA receptor function. H.Y. is

principal investigator on a research grant from Sage Therapeutics to Emory University School of Medicine. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard

to jurisdictional claims in published maps and institutional affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION Supplementary Figs. 1–11, Supplementary Tables 1–12 and

Synthetic Procedures. REPORTING SUMMARY RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Perszyk, R.E., Swanger, S.A., Shelley, C. _et al._ Biased

modulators of NMDA receptors control channel opening and ion selectivity. _Nat Chem Biol_ 16, 188–196 (2020). https://doi.org/10.1038/s41589-019-0449-5 Download citation * Received: 28

December 2018 * Revised: 08 November 2019 * Accepted: 04 December 2019 * Published: 20 January 2020 * Issue Date: February 2020 * DOI: https://doi.org/10.1038/s41589-019-0449-5 SHARE THIS

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