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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...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi Publishing Corporation
2012
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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. |
format | Online Article Text |
id | pubmed-3529497 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
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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