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Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes

The number of N-Methyl-D-aspartate receptor (NMDAR) linked neurodegenerative diseases such as Alzheimer’s disease and dementia is constantly increasing. This is partly due to demographic change and presents new challenges to societies. To date, there are no effective treatment options. Current medic...

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Autores principales: Ritter, Nadine, Disse, Paul, Wünsch, Bernhard, Seebohm, Guiscard, Strutz-Seebohm, Nathalie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10216354/
https://www.ncbi.nlm.nih.gov/pubmed/37239037
http://dx.doi.org/10.3390/biomedicines11051367
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author Ritter, Nadine
Disse, Paul
Wünsch, Bernhard
Seebohm, Guiscard
Strutz-Seebohm, Nathalie
author_facet Ritter, Nadine
Disse, Paul
Wünsch, Bernhard
Seebohm, Guiscard
Strutz-Seebohm, Nathalie
author_sort Ritter, Nadine
collection PubMed
description The number of N-Methyl-D-aspartate receptor (NMDAR) linked neurodegenerative diseases such as Alzheimer’s disease and dementia is constantly increasing. This is partly due to demographic change and presents new challenges to societies. To date, there are no effective treatment options. Current medications are nonselective and can lead to unwanted side effects in patients. A promising therapeutic approach is the targeted inhibition of NMDARs in the brain. NMDARs containing different subunits and splice variants display different physiological properties and play a crucial role in learning and memory, as well as in inflammatory or injury processes. They become overactivated during the course of the disease, leading to nerve cell death. Until now, there has been a lack of understanding of the general functions of the receptor and the mechanism of inhibition, which need to be understood in order to develop inhibitors. Ideal compounds should be highly targeted and even splice-variant-selective. However, a potent and splice-variant-selective NMDAR-targeting drug has yet to be developed. Recently developed 3-benzazepines are promising inhibitors for further drug development. The NMDAR splice variants GluN1-1b-4b carry a 21-amino-acid-long, flexible exon 5. Exon 5 lowers the NMDAR’s sensitivity to allosteric modulators by probably acting as an NMDAR modulator itself. The role of exon 5 in NMDAR modulation is still poorly understood. In this review, we summarize the structure and pharmacological relevance of tetrahydro-3-benzazepines.
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spelling pubmed-102163542023-05-27 Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes Ritter, Nadine Disse, Paul Wünsch, Bernhard Seebohm, Guiscard Strutz-Seebohm, Nathalie Biomedicines Review The number of N-Methyl-D-aspartate receptor (NMDAR) linked neurodegenerative diseases such as Alzheimer’s disease and dementia is constantly increasing. This is partly due to demographic change and presents new challenges to societies. To date, there are no effective treatment options. Current medications are nonselective and can lead to unwanted side effects in patients. A promising therapeutic approach is the targeted inhibition of NMDARs in the brain. NMDARs containing different subunits and splice variants display different physiological properties and play a crucial role in learning and memory, as well as in inflammatory or injury processes. They become overactivated during the course of the disease, leading to nerve cell death. Until now, there has been a lack of understanding of the general functions of the receptor and the mechanism of inhibition, which need to be understood in order to develop inhibitors. Ideal compounds should be highly targeted and even splice-variant-selective. However, a potent and splice-variant-selective NMDAR-targeting drug has yet to be developed. Recently developed 3-benzazepines are promising inhibitors for further drug development. The NMDAR splice variants GluN1-1b-4b carry a 21-amino-acid-long, flexible exon 5. Exon 5 lowers the NMDAR’s sensitivity to allosteric modulators by probably acting as an NMDAR modulator itself. The role of exon 5 in NMDAR modulation is still poorly understood. In this review, we summarize the structure and pharmacological relevance of tetrahydro-3-benzazepines. MDPI 2023-05-05 /pmc/articles/PMC10216354/ /pubmed/37239037 http://dx.doi.org/10.3390/biomedicines11051367 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Ritter, Nadine
Disse, Paul
Wünsch, Bernhard
Seebohm, Guiscard
Strutz-Seebohm, Nathalie
Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes
title Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes
title_full Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes
title_fullStr Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes
title_full_unstemmed Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes
title_short Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes
title_sort pharmacological potential of 3-benzazepines in nmdar-linked pathophysiological processes
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10216354/
https://www.ncbi.nlm.nih.gov/pubmed/37239037
http://dx.doi.org/10.3390/biomedicines11051367
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