HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Free Full Text (PDF) Free All Versions of this Article: fj.08-112227v1 22/12/4209    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Albiston, A. L. Articles by Chai, S. Y. Search for Related Content PubMed PubMed Citation Articles by Albiston, A. L. Articles by Chai, S. Y.

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

Anthony L. Albiston^*, Craig J. Morton, Hooi Ling Ng, Vi Pham^*, Holly R. Yeatman^*, Siying Ye^*,1, Ruani N. Fernando^*,2, Dimitri De Bundel^*,3, David B. Ascher, Frederick A. O. Mendelsohn^*, Michael W. Parker^,,4 and Siew Yeen Chai^*,,4,5

^* Howard Florey Institute, Florey Neurosciences Institutes,

Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, and

Centre for Neuroscience, University of Melbourne, Parkville, Victoria, Australia; and

St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia

⁵ Correspondence: Howard Florey Institute, University of Melbourne, Parkville, VIC 3010, Australia. E-mail: sychai{at}florey.edu.au

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 (K_i 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.—Albiston, A. L., Morton, C. J., Ng, H. L., Pham, V., Yeatman, H. R., Ye, S., Ruani, N., Fernando, R. N., De Bundel, D., Ascher, D. B., Mendelsohn, F. A. O., Parker, M. W., Chai, S. Y. Identification and characterization of a new cognitive enhancer based on inhibition of insulin-regulated aminopeptidase.

Key Words: facilitation of memory • drug development • virtual screening • homology model • glucose uptake