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.