PT - JOURNAL ARTICLE AU - Alene T. McCoy AU - Caroline C. Benoist AU - John W. Wright AU - Leen H. Kawas AU - Jyote M. Bule-Ghogare AU - Mingyan Zhu AU - Suzanne M. Appleyard AU - Gary A. Wayman AU - Joseph W. Harding TI - Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents AID - 10.1124/jpet.112.199497 DP - 2013 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 141--154 VI - 344 IP - 1 4099 - http://jpet.aspetjournals.org/content/344/1/141.short 4100 - http://jpet.aspetjournals.org/content/344/1/141.full SO - J Pharmacol Exp Ther2013 Jan 01; 344 AB - 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.