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New Coumarin Derivatives as Cholinergic and Cannabinoid System Modulators

In the last years, the connection between the endocannabinoid system (eCS) and neuroprotection has been discovered, and evidence indicates that eCS signaling is involved in the regulation of cognitive processes and in the pathophysiology of Alzheimer’s disease (AD). Accordingly, pharmacotherapy targ...

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Autores principales: Montanari, Serena, Allarà, Marco, Scalvini, Laura, Kostrzewa, Magdalena, Belluti, Federica, Gobbi, Silvia, Naldi, Marina, Rivara, Silvia, Bartolini, Manuela, Ligresti, Alessia, Bisi, Alessandra, Rampa, Angela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198714/
https://www.ncbi.nlm.nih.gov/pubmed/34071439
http://dx.doi.org/10.3390/molecules26113254
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author Montanari, Serena
Allarà, Marco
Scalvini, Laura
Kostrzewa, Magdalena
Belluti, Federica
Gobbi, Silvia
Naldi, Marina
Rivara, Silvia
Bartolini, Manuela
Ligresti, Alessia
Bisi, Alessandra
Rampa, Angela
author_facet Montanari, Serena
Allarà, Marco
Scalvini, Laura
Kostrzewa, Magdalena
Belluti, Federica
Gobbi, Silvia
Naldi, Marina
Rivara, Silvia
Bartolini, Manuela
Ligresti, Alessia
Bisi, Alessandra
Rampa, Angela
author_sort Montanari, Serena
collection PubMed
description In the last years, the connection between the endocannabinoid system (eCS) and neuroprotection has been discovered, and evidence indicates that eCS signaling is involved in the regulation of cognitive processes and in the pathophysiology of Alzheimer’s disease (AD). Accordingly, pharmacotherapy targeting eCS could represent a valuable contribution in fighting a multifaceted disease such as AD, opening a new perspective for the development of active agents with multitarget potential. In this paper, a series of coumarin-based carbamic and amide derivatives were designed and synthesized as multipotent compounds acting on cholinergic system and eCS-related targets. Indeed, they were tested with appropriate enzymatic assays on acetyl and butyryl-cholinesterases and on fatty acid amide hydrolase (FAAH), and also evaluated as cannabinoid receptor (CB1 and CB2) ligands. Moreover, their ability to reduce the self-aggregation of beta amyloid protein (Aβ(42)) was assessed. Compounds 2 and 3, bearing a carbamate function, emerged as promising inhibitors of hAChE, hBuChE, FAAH and Aβ(42) self-aggregation, albeit with moderate potencies, while the amide 6 also appears a promising CB1/CB2 receptors ligand. These data prove for the new compounds an encouraging multitarget profile, deserving further evaluation.
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spelling pubmed-81987142021-06-14 New Coumarin Derivatives as Cholinergic and Cannabinoid System Modulators Montanari, Serena Allarà, Marco Scalvini, Laura Kostrzewa, Magdalena Belluti, Federica Gobbi, Silvia Naldi, Marina Rivara, Silvia Bartolini, Manuela Ligresti, Alessia Bisi, Alessandra Rampa, Angela Molecules Article In the last years, the connection between the endocannabinoid system (eCS) and neuroprotection has been discovered, and evidence indicates that eCS signaling is involved in the regulation of cognitive processes and in the pathophysiology of Alzheimer’s disease (AD). Accordingly, pharmacotherapy targeting eCS could represent a valuable contribution in fighting a multifaceted disease such as AD, opening a new perspective for the development of active agents with multitarget potential. In this paper, a series of coumarin-based carbamic and amide derivatives were designed and synthesized as multipotent compounds acting on cholinergic system and eCS-related targets. Indeed, they were tested with appropriate enzymatic assays on acetyl and butyryl-cholinesterases and on fatty acid amide hydrolase (FAAH), and also evaluated as cannabinoid receptor (CB1 and CB2) ligands. Moreover, their ability to reduce the self-aggregation of beta amyloid protein (Aβ(42)) was assessed. Compounds 2 and 3, bearing a carbamate function, emerged as promising inhibitors of hAChE, hBuChE, FAAH and Aβ(42) self-aggregation, albeit with moderate potencies, while the amide 6 also appears a promising CB1/CB2 receptors ligand. These data prove for the new compounds an encouraging multitarget profile, deserving further evaluation. MDPI 2021-05-28 /pmc/articles/PMC8198714/ /pubmed/34071439 http://dx.doi.org/10.3390/molecules26113254 Text en © 2021 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 Article
Montanari, Serena
Allarà, Marco
Scalvini, Laura
Kostrzewa, Magdalena
Belluti, Federica
Gobbi, Silvia
Naldi, Marina
Rivara, Silvia
Bartolini, Manuela
Ligresti, Alessia
Bisi, Alessandra
Rampa, Angela
New Coumarin Derivatives as Cholinergic and Cannabinoid System Modulators
title New Coumarin Derivatives as Cholinergic and Cannabinoid System Modulators
title_full New Coumarin Derivatives as Cholinergic and Cannabinoid System Modulators
title_fullStr New Coumarin Derivatives as Cholinergic and Cannabinoid System Modulators
title_full_unstemmed New Coumarin Derivatives as Cholinergic and Cannabinoid System Modulators
title_short New Coumarin Derivatives as Cholinergic and Cannabinoid System Modulators
title_sort new coumarin derivatives as cholinergic and cannabinoid system modulators
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198714/
https://www.ncbi.nlm.nih.gov/pubmed/34071439
http://dx.doi.org/10.3390/molecules26113254
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