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Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
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2016 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 7, no 10, 1383-1392 p.Article in journal (Refereed) Published
Abstract [en]

The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of TRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors:A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons.

Place, publisher, year, edition, pages
2016. Vol. 7, no 10, 1383-1392 p.
Keyword [en]
Insulin-regulated aminopeptidase, aryl sulfonamides, molecular dynamics, ligand interaction energy simulations, dendritic spines, hippocampal neurons
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-307715DOI: 10.1021/acschemneuro.6b00146ISI: 000385994000011OAI: oai:DiVA.org:uu-307715DiVA: diva2:1048717
Funder
Swedish Research Council
Available from: 2016-11-22 Created: 2016-11-21 Last updated: 2016-11-22Bibliographically approved

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Nylander, ErikGrönbladh, AlfhildVanga, Sudarsana ReddyKhan, Yasmin ShamsudinGutierrez-de-Teran, HugoSävmarker, JonasSvensson, RichardArtursson, PerZelleroth, SofiaEngen, KarinRosenström, UlrikaLarhed, MatsÅqvist, JohanHallberg, Mathias
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Department of Pharmaceutical BiosciencesComputational Biology and BioinformaticsOrganic Pharmaceutical ChemistryDepartment of PharmacyScience for Life Laboratory, SciLifeLabDivision of Molecular Imaging
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