Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents.
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.
Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, P.O. Box 6520, Washington State University, Pullman, WA 99164-6520, USA.
Alene T
AT
McCoy
Caroline C
CC
Benoist
John W
JW
Wright
Leen H
LH
Kawas
Jyote M
JM
Bule-Ghogare
Mingyan
M
Zhu
Suzanne M
SM
Appleyard
Gary A
GA
Wayman
Joseph W
JW
Harding
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003704:Dementia / Q000517:prevention & control*; D049229:Dendritic Spines / Q000187:drug effects; D006207:Half-Life; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006860:Hydrogen Bonding; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D018697:Nootropic Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet; D013569:Synapses / Q000187:drug effects; D014162:Transfection
D018697:Nootropic Agents; D009842:Oligopeptides; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; C578458:N-hexanoic-Tyr-Ile-(6) aminohexanoic amide