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, norleucine1-angiotensin IV, resides in its three N-terminal amino acids, Nle-Tyr-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, blood-barrier permeant, metabolically stabilized analog, N-hexanoic-Tyr-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.
Footnotes
A.T.M., C.C.B., and J.W.W. contributed equally to the generation and presentation of the data described in this study.
This work was supported in part by the Edward E. and Lucille I. Lainge Endowment for Alzheimer’s Research, funds provided for medical and biological research by the State of Washington Initiative Measure No. 171 to J.W.W.; the National Institutes of Health [Grant MH086032]; and a Hope for Depression Research Foundation grant to G.A.W.
J.W.W. and J.W.H. are founders and shareholders of M3 Biotechnology, LLC, which is developing pharmaceuticals based on this technology.
An abstract of part of this work has appeared at the following meeting: Benoist CC, Wright JW, Zhu M, Kawas LH, Appleyard SA, Wayman GA, and Harding JW (2010) Evaluation of an orally active angiotensin IV analogue (Abstract #856.3). Society for Neuroscience Meeting; 2010; San Diego, CA.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Received August 22, 2012.
- Accepted October 9, 2012.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|