Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents

Abstract

Angiotensin IV (AngIV: VYIHPF)-related peptides have long been recognized as procognitive agents with potential as antidementia therapeutics. Their development as useful therapeutics, however, has been limited by physiochemical properties that make them susceptible to metabolic degradation and impermeable to gut and blood-brain barriers. A previous study demonstrated that the core structural information required to impart the procognitive activity of the AngIV analog, norleucine 1 -angiotensin IV, resides in its three N-terminal amino acids, NleTyr-Ile. The goal of this project was to chemically modify this tripeptide in such a way to enhance its metabolic stability and barrier permeability to produce a drug candidate with potential clinical utility. Initial results demonstrated that several N-and C-terminal modifications lead to dramatically improved stability while maintaining the capability to reverse scopolamine-induced deficits in Morris water maze performance and augment hippocampal synaptogenesis. Subsequent chemical modifications, which were designed to increase hydrophobicity and decrease hydrogen bonding, yielded an orally active, bloodbarrier permeant, metabolically stabilized analog, N-hexanoicTyr-Ile-(6) aminohexanoic amide (dihexa), that exhibits excellent antidementia activity in the scopolamine and aged rat models and marked synaptogenic activity. These data suggest that dihexa may have therapeutic potential as a treatment of disorders, such as Alzheimer's disease, where augmented synaptic connectivity may be beneficial.

Binding to and Inhibition of Insulin-Regulated Aminopeptidase by Macrocyclic Disulfides Enhances Spine Density

“…In contrast, HA09 did not alter total spine density or morphology compared with the vehicle control. Given that previous studies have shown that the procognitive activity of a molecule in vivo correlates well with its in vitro ability to alter dendritic spine structure (Benoist et al, 2011;McCoy et al, 2013), these results suggest that HA08 may have cognitive enhancing effects.…”

“…Previous studies have observed a correlation between the procognitive effects of Ang IV-derived peptides in rodents and their capacities to increase spine number and alter morphology (Benoist et al, 2011;McCoy et al, 2013). These data suggest that the positive impact of these peptides and peptidomimetics on cognition and dendritic spines might be attributed to a possible capacity to suppress the catalytic activity of the aminopeptidase IRAP.…”

“…There is a need for improved cognitive enhancers for the treatment of Alzheimer's disease and related disorders and it is therefore not surprising that considerable efforts have been devoted to the discovery of compounds that can mimic the positive effects of Ang IV (Wolfe, 2002;Chai et al, 2008;Gard, 2008;Wright et al, 2008Hallberg, 2009;Kawas et al, 2012;McCoy et al, 2013). Both potent and specific drug-like IRAP inhibitors (Borhade et al, 2014;Mountford et al, 2014), some with proven effects in vivo (Albiston et al, , 2011, and inhibitors with more peptidic character (Kobori et al, , 1998Wolfe, 2002;Axen et al, 2006;Axen et al, 2007;Andersson et al, 2008;Lukaszuk et al, 2008Lukaszuk et al, , 2009Hallberg, 2009) have been disclosed by us and others.…”

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

“…As for AT4, the identification of small but critically important peptide fragments [258] and their N-and C-terminal modifications led to the development of the selective AT4 agonist N-hexanoic-Tyr-Ile-(6) aminohexanoic amide. This molecule was sufficiently bloodbrain barrier permeable to have precognitive effects in Morris water maze performance [259]. Experiments using selective AT4 agonists are needed in the future to address their anti-convulsive actions.…”

The Procognitive and Synaptogenic Effects of Angiotensin IV–Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System

“…Nle 1 -AngIV, an often-employed AT 4 receptor agonist with demonstrated procognitive activity (Benoist et al, 2011), along with its metabolically stabilized and orally active derivative, N-hexanoic-tyrosine-isoleucine-(6) aminohexanoic amide (dihexa) (McCoy et al, 2013), were utilized to probe this question. Both agonists were found to potentiate the cellular actions of HGF.…”