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Discovery of Inhibitors of Insulin-Regulated Aminopeptidase as Cognitive Enhancers

The hexapeptide angiotensin IV (Ang IV) is a metabolite of angiotensin II (Ang II) and plays a central role in the brain. It was reported more than two decades ago that intracerebroventricular injection of Ang IV improved memory and learning in the rat. Several hypotheses have been put forward to ex...

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Detalles Bibliográficos
Autores principales: Andersson, Hanna, Hallberg, Mathias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi Publishing Corporation 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529497/
https://www.ncbi.nlm.nih.gov/pubmed/23304452
http://dx.doi.org/10.1155/2012/789671
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author Andersson, Hanna
Hallberg, Mathias
author_facet Andersson, Hanna
Hallberg, Mathias
author_sort Andersson, Hanna
collection PubMed
description The hexapeptide angiotensin IV (Ang IV) is a metabolite of angiotensin II (Ang II) and plays a central role in the brain. It was reported more than two decades ago that intracerebroventricular injection of Ang IV improved memory and learning in the rat. Several hypotheses have been put forward to explain the positive effects of Ang IV and related analogues on cognition. It has been proposed that the insulin-regulated aminopeptidase (IRAP) is the main target of Ang IV. This paper discusses progress in the discovery of inhibitors of IRAP as potential enhancers of cognitive functions. Very potent inhibitors of the protease have been synthesised, but pharmacokinetic issues (including problems associated with crossing the blood-brain barrier) remain to be solved. The paper also briefly presents an overview of the status in the discovery of inhibitors of ACE and renin, and of AT1R antagonists and AT2R agonists, in order to enable other discovery processes within the RAS system to be compared. The paper focuses on the relationship between binding affinities/inhibition capacity and the structures of the ligands that interact with the target proteins.
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spelling pubmed-35294972013-01-09 Discovery of Inhibitors of Insulin-Regulated Aminopeptidase as Cognitive Enhancers Andersson, Hanna Hallberg, Mathias Int J Hypertens Review Article The hexapeptide angiotensin IV (Ang IV) is a metabolite of angiotensin II (Ang II) and plays a central role in the brain. It was reported more than two decades ago that intracerebroventricular injection of Ang IV improved memory and learning in the rat. Several hypotheses have been put forward to explain the positive effects of Ang IV and related analogues on cognition. It has been proposed that the insulin-regulated aminopeptidase (IRAP) is the main target of Ang IV. This paper discusses progress in the discovery of inhibitors of IRAP as potential enhancers of cognitive functions. Very potent inhibitors of the protease have been synthesised, but pharmacokinetic issues (including problems associated with crossing the blood-brain barrier) remain to be solved. The paper also briefly presents an overview of the status in the discovery of inhibitors of ACE and renin, and of AT1R antagonists and AT2R agonists, in order to enable other discovery processes within the RAS system to be compared. The paper focuses on the relationship between binding affinities/inhibition capacity and the structures of the ligands that interact with the target proteins. Hindawi Publishing Corporation 2012 2012-12-04 /pmc/articles/PMC3529497/ /pubmed/23304452 http://dx.doi.org/10.1155/2012/789671 Text en Copyright © 2012 H. Andersson and M. Hallberg. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Review Article
Andersson, Hanna
Hallberg, Mathias
Discovery of Inhibitors of Insulin-Regulated Aminopeptidase as Cognitive Enhancers
title Discovery of Inhibitors of Insulin-Regulated Aminopeptidase as Cognitive Enhancers
title_full Discovery of Inhibitors of Insulin-Regulated Aminopeptidase as Cognitive Enhancers
title_fullStr Discovery of Inhibitors of Insulin-Regulated Aminopeptidase as Cognitive Enhancers
title_full_unstemmed Discovery of Inhibitors of Insulin-Regulated Aminopeptidase as Cognitive Enhancers
title_short Discovery of Inhibitors of Insulin-Regulated Aminopeptidase as Cognitive Enhancers
title_sort discovery of inhibitors of insulin-regulated aminopeptidase as cognitive enhancers
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529497/
https://www.ncbi.nlm.nih.gov/pubmed/23304452
http://dx.doi.org/10.1155/2012/789671
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