Binding to and Inhibition of Insulin-Regulated Aminopeptidase by Macrocyclic Disulfides Enhances Spine Density
Shanti Diwakarla, Erik Nylander, Alfhild Gronbladh, Sudarsana Reddy Vanga, Yasmin Shamsudin Khan, Hugo Gutierrez-de-Teran, Leelee Ng, Pham Vi, Jonas Savmarker, Thomas Lundback, Annika Jenmalm-Jensen, Hanna Andersson, Karin Engen, Ulrika Rosenstrom, Mats Larhed, Johan Aqvist, Siew Yeen Chai, Mathias Hallberg
MOLECULAR PHARMACOLOGY | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS | Published : 2016
Angiotensin IV (Ang IV) and related peptide analogs, as well as nonpeptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocyclic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N terminus of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors ..View full abstract
This work was supported by grants from the Swedish Research Council to the Department of Pharmaceutical Biosciences, the Department of Medicinal Chemistry, and the Department of Cell and Molecular Biology, and from the Kjell and Marta Beijer Foundation to the Department of Pharmaceutical Biosciences and to the Department of Medicinal Chemistry at Uppsala University.