title: The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases.
abstract: Alzheimer's (AD) and Parkinson's (PD) diseases are neurodegenerative diseases presently without effective drug treatments. AD is characterized by general cognitive impairment, difficulties with memory consolidation and retrieval, and with advanced stages episodes of agitation and anger. AD is increasing in frequency as life expectancy increases. Present FDA approved medications do little to slow disease progression and none address the underlying progressive loss of synaptic connections and neurons. New drug design approaches are needed beyond cholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists. Patients with PD experience the symptomatic triad of bradykinesis, tremor-at-rest, and rigidity with the possibility of additional non-motor symptoms including sleep disturbances, depression, dementia, and autonomic nervous system failure. This review summarizes available information regarding the role of the brain renin-angiotensin system (RAS) in learning and memory and motor functions, with particular emphasis on research results suggesting a link between angiotensin IV (AngIV) interacting with the AT4 receptor subtype. Currently there is controversy over the identity of this AT4 receptor protein. Albiston and colleagues have offered convincing evidence that it is the insulin-regulated aminopeptidase (IRAP). Recently members of our laboratory have presented evidence that the brain AngIV/AT4 receptor system coincides with the brain hepatocyte growth factor/c-Met receptor system. In an effort to resolve this issue we have synthesized a number of small molecule AngIV-based compounds that are metabolically stable, penetrate the blood-brain barrier, and facilitate compromised memory and motor systems. These research efforts are described along with details concerning a recently synthesized molecule, Dihexa that shows promise in overcoming memory and motor dysfunctions by augmenting synaptic connectivity via the formation of new functional synapses.
authors.affiliation: Departments of Psychology, Integrative Physiology and Neuroscience and Program in Biotechnology, Washington State University, Pullman, WA 99164-4820, USA; M3 Biotechnology, Inc., 4000 Mason Rd Suite 300, Box 352141, Seattle, WA 98195-2141, USA. Electronic address: wrightjw@wsu.edu.
authors.forename: John W
authors.initials: JW
authors.lastname: Wright
authors.affiliation: Departments of Psychology, Integrative Physiology and Neuroscience and Program in Biotechnology, Washington State University, Pullman, WA 99164-4820, USA; M3 Biotechnology, Inc., 4000 Mason Rd Suite 300, Box 352141, Seattle, WA 98195-2141, USA.
authors.forename: Leen H
authors.initials: LH
authors.lastname: Kawas
authors.affiliation: Departments of Psychology, Integrative Physiology and Neuroscience and Program in Biotechnology, Washington State University, Pullman, WA 99164-4820, USA; M3 Biotechnology, Inc., 4000 Mason Rd Suite 300, Box 352141, Seattle, WA 98195-2141, USA.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Harding
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy*; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D006801:Humans; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology; D010300:Parkinson Disease / Q000150:complications / Q000188:drug therapy*; D011945:Receptors, Angiotensin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology
chemical_list: C090830:AT4 receptor; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-
keywords: AT(4) receptor subtype; Alzheimer's disease; Angiotensin IV; Dihexa; Hepatocyte growth factor; Parkinson's disease; c-Met receptor