Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents

Alene T McCoy; Caroline C Benoist; John W Wright; Leen H Kawas; Jyote M Bule-Ghogare; Mingyan Zhu; Suzanne M Appleyard; Gary A Wayman; Joseph W Harding

doi:10.1124/jpet.112.199497

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Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents

Journal article

Open access

Peer reviewed

Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents

Alene T McCoy, Caroline C Benoist, John W Wright, Leen H Kawas, Jyote M Bule-Ghogare, Mingyan Zhu, Suzanne M Appleyard, Gary A Wayman and Joseph W Harding

The Journal of pharmacology and experimental therapeutics, Vol.344(1), pp.141-154

01/2013

DOI: https://doi.org/10.1124/jpet.112.199497

Handle:

https://hdl.handle.net/2376/100276

PMCID: PMC3533412

PMID: 23055539

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https://doi.org/10.1124/jpet.112.199497View

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Abstract

Immunohistochemistry

Microsomes, Liver - metabolism

Half-Life

Male

Chromatography, High Pressure Liquid

Hippocampus - drug effects

Transfection

Dendritic Spines - drug effects

Microsomes, Liver - drug effects

Neurogenesis - drug effects

Synapses - drug effects

Angiotensin II - pharmacology

Angiotensin II - metabolism

Rats

Angiotensin II - analogs & derivatives

Oligopeptides - metabolism

Hippocampus - cytology

Maze Learning - drug effects

Rats, Sprague-Dawley

Spectrophotometry, Ultraviolet

Blood-Brain Barrier - metabolism

Patch-Clamp Techniques

Animals

Hydrogen Bonding

In Vitro Techniques

Oligopeptides - pharmacology

Dementia - prevention & control

Nootropic Agents - pharmacology

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, 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.

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Title: Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents
Creators: Alene T McCoy - Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, P.O. Box 6520, Washington State University, Pullman, WA 99164-6520, USA
Caroline C Benoist
John W Wright
Leen H Kawas
Jyote M Bule-Ghogare
Mingyan Zhu
Suzanne M Appleyard
Gary A Wayman
Joseph W Harding
Publication Details: The Journal of pharmacology and experimental therapeutics, Vol.344(1), pp.141-154
Academic Unit: Psychology, Department of; Integrative Physiology and Neuroscience, Department of
Publisher: United States
Grant note: MH086032 / NIMH NIH HHS R01 MH086032 / NIMH NIH HHS
Identifiers: 99900546540901842
Language: English
Resource Type: Journal article