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Research ArticleDrug Discovery and Translational Medicine

Evaluation of metabolically stabilized angiotensin IV analogs as pro-cognitive/anti-dementia agents

Alene T McCoy, Caroline C Benoist, John W Wright, Leen H Kawas, Jyote Bule-Ghogare, Mingyan Zhu, Suzanne M Appleyard, Gary A Wayman and Joseph W Harding
Journal of Pharmacology and Experimental Therapeutics October 10, 2012, jpet.112.199497; DOI: https://doi.org/10.1124/jpet.112.199497
Alene T McCoy
1 The Dow Chemical Company;
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Caroline C Benoist
2 Vanderbilt University;
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John W Wright
3 Washington State University
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Leen H Kawas
3 Washington State University
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Jyote Bule-Ghogare
3 Washington State University
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Mingyan Zhu
3 Washington State University
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Suzanne M Appleyard
3 Washington State University
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Gary A Wayman
3 Washington State University
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Joseph W Harding
3 Washington State University
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Abstract

Angiotensin IV (AngIV: VYIHPF) related peptides have long been recognized as pro-cognitive agents with potential as anti-dementia therapeutics. Their development as useful therapeutics, however, has been limited by susceptibility to metabolic degradation and physiochemical properties that make them impermeable to gut and blood-brain barriers. A previous study has demonstrated that the core structural information required to impart the pro-cognitive activity of the AngIV analog, Norleucine1-angiotensin IV (Nle1-AngIV), 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 as to enhance its metabolic stability and membrane 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-brain barrier permeant, metabolically stabilized analog, N-hexanoic-Tyr, Ile-(6) aminohexanoic amide ( Dihexa) that exhibits excellent anti-dementia activity in the scopolamine and aged rat models and marked synaptogenic activity. These data suggest that Dihexa may have therapeutic potential as a treatment for disorders, like Alzheimer's disease, where augmented synaptic connectivity may be beneficial.

  • cognition
  • dementia
  • drug development
  • growth factors
  • synaptic plasticity
  • Received August 22, 2012.
  • Revision received October 5, 2012.
  • Accepted October 9, 2012.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleDrug Discovery and Translational Medicine

Evaluation of metabolically stabilized angiotensin IV analogs as pro-cognitive/anti-dementia agents

Alene T McCoy, Caroline C Benoist, John W Wright, Leen H Kawas, Jyote Bule-Ghogare, Mingyan Zhu, Suzanne M Appleyard, Gary A Wayman and Joseph W Harding
Journal of Pharmacology and Experimental Therapeutics October 10, 2012, jpet.112.199497; DOI: https://doi.org/10.1124/jpet.112.199497

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Research ArticleDrug Discovery and Translational Medicine

Evaluation of metabolically stabilized angiotensin IV analogs as pro-cognitive/anti-dementia agents

Alene T McCoy, Caroline C Benoist, John W Wright, Leen H Kawas, Jyote Bule-Ghogare, Mingyan Zhu, Suzanne M Appleyard, Gary A Wayman and Joseph W Harding
Journal of Pharmacology and Experimental Therapeutics October 10, 2012, jpet.112.199497; DOI: https://doi.org/10.1124/jpet.112.199497
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