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Identification and characterization of a new class of cognitive enhancers based on inhibition of insulin-regulated aminopeptidase

Albiston, Anthony L., Morton, Craig J., Ng, Hooi Ling, Pham, Vi, Yeatman, Holly R., Ye, Siying, Fernando, Ruani N., De Bundel, Dimitri, Ascher, David B., Mendelsohn, Frederick A. O., Parker, Michael W. and Chai, Siew Yeen 2008, Identification and characterization of a new class of cognitive enhancers based on inhibition of insulin-regulated aminopeptidase, FASEB journal, vol. 22, no. 12, pp. 4209-4217, doi: 10.1096/fj.08-112227.

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Title Identification and characterization of a new class of cognitive enhancers based on inhibition of insulin-regulated aminopeptidase
Author(s) Albiston, Anthony L.
Morton, Craig J.
Ng, Hooi Ling
Pham, Vi
Yeatman, Holly R.
Ye, Siying
Fernando, Ruani N.
De Bundel, Dimitri
Ascher, David B.
Mendelsohn, Frederick A. O.
Parker, Michael W.
Chai, Siew Yeen
Journal name FASEB journal
Volume number 22
Issue number 12
Start page 4209
End page 4217
Total pages 9
Publisher Federation of American Societies for Experimental Biology
Place of publication Bethesda, Md.
Publication date 2008-12-01
ISSN 0892-6638
1530-6860
Keyword(s) facilitation of memory
drug development
virtual screening
homology model
glucose uptake
Summary Approximately one-quarter of people over the age of 65 are estimated to suffer some form of cognitive impairment, underscoring the need for effective cognitive-enhancing agents. Insulin-regulated aminopeptidase (IRAP) is potentially an innovative target for the development of cognitive enhancers, as its peptide inhibitors exhibit memory-enhancing effects in both normal and memory-impaired rodents. Using a homology model of the catalytic domain of IRAP and virtual screening, we have identified a class of nonpeptide, small-molecule inhibitors of IRAP. Structure-based computational development of an initial "hit" resulted in the identification of two divergent families of compounds. Subsequent medicinal chemistry performed on the highest affinity compound produced inhibitors with nanomolar affinities (Ki 20–700 nM) for IRAP. In vivo efficacy of one of these inhibitors was demonstrated in rats with an acute dose (1 nmol in 1 µl) administered into the lateral ventricles, improving performance in both spatial working and recognition memory paradigms. We have identified a family of specific IRAP inhibitors that is biologically active which will be useful both in understanding the physiological role of IRAP and potentially in the development of clinically useful cognitive enhancers. Notably, this study also provides unequivocal proof of principal that inhibition of IRAP results in memory enhancement.
Language eng
DOI 10.1096/fj.08-112227
Field of Research 069999 Biological Sciences not elsewhere classified
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2008, FASEB
Persistent URL http://hdl.handle.net/10536/DRO/DU:30040943

Document type: Journal Article
Collection: School of Medicine
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