Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives

N-Methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR has been linked to diseases like Parkinson’s, Alzheimer’s, schizophreni...

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Autores principales: Ritter, Nadine, Disse, Paul, Aymanns, Isabel, Mücher, Lena, Schreiber, Julian A., Brenker, Christoph, Strünker, Timo, Schepmann, Dirk, Budde, Thomas, Strutz-Seebohm, Nathalie, Ametamey, Simon M., Wünsch, Bernhard, Seebohm, Guiscard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10657792/
https://www.ncbi.nlm.nih.gov/pubmed/37542648
http://dx.doi.org/10.1007/s12035-023-03526-1
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author Ritter, Nadine
Disse, Paul
Aymanns, Isabel
Mücher, Lena
Schreiber, Julian A.
Brenker, Christoph
Strünker, Timo
Schepmann, Dirk
Budde, Thomas
Strutz-Seebohm, Nathalie
Ametamey, Simon M.
Wünsch, Bernhard
Seebohm, Guiscard
author_facet Ritter, Nadine
Disse, Paul
Aymanns, Isabel
Mücher, Lena
Schreiber, Julian A.
Brenker, Christoph
Strünker, Timo
Schepmann, Dirk
Budde, Thomas
Strutz-Seebohm, Nathalie
Ametamey, Simon M.
Wünsch, Bernhard
Seebohm, Guiscard
author_sort Ritter, Nadine
collection PubMed
description N-Methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR has been linked to diseases like Parkinson’s, Alzheimer’s, schizophrenia, and drug addiction. The development of selective receptor modulators, therefore, constitutes a promising approach for numerous therapeutical applications. Here, we identified (R)-OF-NB1 as a promising splice variant selective NMDAR antagonist. We investigated the interaction of (R)-OF-NB1 and NMDAR from a biochemical, bioinformatical, and electrophysiological perspective to characterize the downstream allosteric modulation of NMDAR by 3-benzazepine derivatives. The allosteric modulatory pathway starts at the ifenprodil binding pocket in the amino terminal domain and immobilizes the connecting α5-helix to the ligand binding domain, resulting in inhibition. In contrast, the exon 5 splice variant GluN1-1b elevates the NMDARs flexibility and promotes the open state of its ligand binding domain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-023-03526-1.
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spelling pubmed-106577922023-08-05 Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives Ritter, Nadine Disse, Paul Aymanns, Isabel Mücher, Lena Schreiber, Julian A. Brenker, Christoph Strünker, Timo Schepmann, Dirk Budde, Thomas Strutz-Seebohm, Nathalie Ametamey, Simon M. Wünsch, Bernhard Seebohm, Guiscard Mol Neurobiol Article N-Methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR has been linked to diseases like Parkinson’s, Alzheimer’s, schizophrenia, and drug addiction. The development of selective receptor modulators, therefore, constitutes a promising approach for numerous therapeutical applications. Here, we identified (R)-OF-NB1 as a promising splice variant selective NMDAR antagonist. We investigated the interaction of (R)-OF-NB1 and NMDAR from a biochemical, bioinformatical, and electrophysiological perspective to characterize the downstream allosteric modulation of NMDAR by 3-benzazepine derivatives. The allosteric modulatory pathway starts at the ifenprodil binding pocket in the amino terminal domain and immobilizes the connecting α5-helix to the ligand binding domain, resulting in inhibition. In contrast, the exon 5 splice variant GluN1-1b elevates the NMDARs flexibility and promotes the open state of its ligand binding domain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-023-03526-1. Springer US 2023-08-05 2023 /pmc/articles/PMC10657792/ /pubmed/37542648 http://dx.doi.org/10.1007/s12035-023-03526-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Ritter, Nadine
Disse, Paul
Aymanns, Isabel
Mücher, Lena
Schreiber, Julian A.
Brenker, Christoph
Strünker, Timo
Schepmann, Dirk
Budde, Thomas
Strutz-Seebohm, Nathalie
Ametamey, Simon M.
Wünsch, Bernhard
Seebohm, Guiscard
Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives
title Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives
title_full Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives
title_fullStr Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives
title_full_unstemmed Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives
title_short Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives
title_sort downstream allosteric modulation of nmda receptors by 3-benzazepine derivatives
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10657792/
https://www.ncbi.nlm.nih.gov/pubmed/37542648
http://dx.doi.org/10.1007/s12035-023-03526-1
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