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Modulating brain integrative actions as a new perspective on pharmacological approaches to neuropsychiatric diseases

A critical aspect of drug development in the therapy of neuropsychiatric diseases is the “Target Problem”, that is, the selection of a proper target after not simply the etiopathological classification but rather the detection of the supposed structural and/or functional alterations in the brain net...

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Autores principales: Marcoli, Manuela, Agnati, Luigi F., Franco, Rafael, Cortelli, Pietro, Anderlini, Deanna, Guidolin, Diego, Cervetto, Chiara, Maura, Guido
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9868467/
https://www.ncbi.nlm.nih.gov/pubmed/36699033
http://dx.doi.org/10.3389/fendo.2022.1038874
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author Marcoli, Manuela
Agnati, Luigi F.
Franco, Rafael
Cortelli, Pietro
Anderlini, Deanna
Guidolin, Diego
Cervetto, Chiara
Maura, Guido
author_facet Marcoli, Manuela
Agnati, Luigi F.
Franco, Rafael
Cortelli, Pietro
Anderlini, Deanna
Guidolin, Diego
Cervetto, Chiara
Maura, Guido
author_sort Marcoli, Manuela
collection PubMed
description A critical aspect of drug development in the therapy of neuropsychiatric diseases is the “Target Problem”, that is, the selection of a proper target after not simply the etiopathological classification but rather the detection of the supposed structural and/or functional alterations in the brain networks. There are novel ways of approaching the development of drugs capable of overcoming or at least reducing the deficits without triggering deleterious side effects. For this purpose, a model of brain network organization is needed, and the main aspects of its integrative actions must also be established. Thus, to this aim we here propose an updated model of the brain as a hyper-network in which i) the penta-partite synapses are suggested as key nodes of the brain hyper-network and ii) interacting cell surface receptors appear as both decoders of signals arriving to the network and targets of central nervous system diseases. The integrative actions of the brain networks follow the “Russian Doll organization” including the micro (i.e., synaptic) and nano (i.e., molecular) levels. In this scenario, integrative actions result primarily from protein-protein interactions. Importantly, the macromolecular complexes arising from these interactions often have novel structural binding sites of allosteric nature. Taking G protein-coupled receptors (GPCRs) as potential targets, GPCRs heteromers offer a way to increase the selectivity of pharmacological treatments if proper allosteric drugs are designed. This assumption is founded on the possible selectivity of allosteric interventions on G protein-coupled receptors especially when organized as “Receptor Mosaics” at penta-partite synapse level.
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spelling pubmed-98684672023-01-24 Modulating brain integrative actions as a new perspective on pharmacological approaches to neuropsychiatric diseases Marcoli, Manuela Agnati, Luigi F. Franco, Rafael Cortelli, Pietro Anderlini, Deanna Guidolin, Diego Cervetto, Chiara Maura, Guido Front Endocrinol (Lausanne) Endocrinology A critical aspect of drug development in the therapy of neuropsychiatric diseases is the “Target Problem”, that is, the selection of a proper target after not simply the etiopathological classification but rather the detection of the supposed structural and/or functional alterations in the brain networks. There are novel ways of approaching the development of drugs capable of overcoming or at least reducing the deficits without triggering deleterious side effects. For this purpose, a model of brain network organization is needed, and the main aspects of its integrative actions must also be established. Thus, to this aim we here propose an updated model of the brain as a hyper-network in which i) the penta-partite synapses are suggested as key nodes of the brain hyper-network and ii) interacting cell surface receptors appear as both decoders of signals arriving to the network and targets of central nervous system diseases. The integrative actions of the brain networks follow the “Russian Doll organization” including the micro (i.e., synaptic) and nano (i.e., molecular) levels. In this scenario, integrative actions result primarily from protein-protein interactions. Importantly, the macromolecular complexes arising from these interactions often have novel structural binding sites of allosteric nature. Taking G protein-coupled receptors (GPCRs) as potential targets, GPCRs heteromers offer a way to increase the selectivity of pharmacological treatments if proper allosteric drugs are designed. This assumption is founded on the possible selectivity of allosteric interventions on G protein-coupled receptors especially when organized as “Receptor Mosaics” at penta-partite synapse level. Frontiers Media S.A. 2023-01-09 /pmc/articles/PMC9868467/ /pubmed/36699033 http://dx.doi.org/10.3389/fendo.2022.1038874 Text en Copyright © 2023 Marcoli, Agnati, Franco, Cortelli, Anderlini, Guidolin, Cervetto and Maura https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Marcoli, Manuela
Agnati, Luigi F.
Franco, Rafael
Cortelli, Pietro
Anderlini, Deanna
Guidolin, Diego
Cervetto, Chiara
Maura, Guido
Modulating brain integrative actions as a new perspective on pharmacological approaches to neuropsychiatric diseases
title Modulating brain integrative actions as a new perspective on pharmacological approaches to neuropsychiatric diseases
title_full Modulating brain integrative actions as a new perspective on pharmacological approaches to neuropsychiatric diseases
title_fullStr Modulating brain integrative actions as a new perspective on pharmacological approaches to neuropsychiatric diseases
title_full_unstemmed Modulating brain integrative actions as a new perspective on pharmacological approaches to neuropsychiatric diseases
title_short Modulating brain integrative actions as a new perspective on pharmacological approaches to neuropsychiatric diseases
title_sort modulating brain integrative actions as a new perspective on pharmacological approaches to neuropsychiatric diseases
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9868467/
https://www.ncbi.nlm.nih.gov/pubmed/36699033
http://dx.doi.org/10.3389/fendo.2022.1038874
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