Science, Serendipity and New Discoveries

1. Science, Serendipity and New Discoveries Jay Wright and Joe Harding

2. Serendipity From the French fairy tale: The Three Princes of Serendipity “The gift of receiving a valuable thing or event not sought for.” ♪ Joe and I met because of a Pullman real estate agent. ♪ We purified the wrong receptor protein. ♪ The Vice-President for Research at Eli Lilly Pharmaceutical found us at a Conference

3. Conversion steps for AngII to AngIII to AngIV Wright & Harding, Progress in Neurobiology 2004, 72:263-293

4. Autoradiogram of AT4 Receptor Subtype Locations in Human Neocortex and Hippocampus Chai et al., J. Chem Neuroanat 2000, 20:339-348.

5. AT4 Receptor Subtype Binding in Neocortex and Hippocampus

6. Categories of Memory • Sensory Memory (a few seconds in duration)

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9. Categories of Memory • Sensory Memory (a few seconds) • Short-term Memory (aka “Working Memory”) • New information is encoded from sensory memory • Working memory holds 7±2 pieces of information for 10-60 sec • Long-term Memory (aka “Reference Memory”) • Once information is encoded it can be stored in long-term memory • Two major subcategories: • Procedural memory (eg motor skills, conditioned responses) • Declarative Memory (eg autobiographical information, factual knowledge, day-to-day inform.)

10. Characteristics of Dementias • Memory impairment (difficulty learning new information, and/or forgetting previously learned material, experiences, recent events) • At least one of the following: • Aphasia (language disturbance) • Apraxia (impaired motor functioning) • Agnosia (failure to recognize familiar objects) • Disturbances ofexecutive function (i.e. abstract thinking, monitoring complex behaviors) Diagnostic and Statistical Manual of Mental Disorders IV, 2000 APA

11. Major Categories of Dementias • Vascular dementia: typically follows cerebrovascular accidents due to ischemic or hemorrhagic damage. (approximately 30% of all dementias) • Alzheimer’s Disease (approximately 50%) • (Dementia affects about one-third of those over 65 years of age.)

12. At present there is no effective treatment for dementia • 4.2 to 5.8 million people with Alzheimer’s disease in US2,3,4 • 16 million in US projected by 20502 (2) Alzheimer’s Foundation of America (3) Decision Resources (4) ResearchandMarkets.com

13. Current FDA approved Anti-Dementia drugs: • Cholinesterase inhibitors: • Cognex (Parke-Davis/Warner-Lambert) ~ $110 per month • Aricept (Eisai) ~ $174 per month • Exelon (Novartis) ~ $220 per month • Reminyl (Jansen) ~ $193 per month • NMDA antagonist: • Namenda (Forest-Lundbeck-Merz) ~ $180-200 per month

14. Causes of Dementia • Dementia is presently thought to be initiated early in life due to risk factors such as: • Elevations in blood pressure • Insulin resistance • Hypercholesterolemia • Cerebrovascular disease

15. Emerging Model of Dementias • Longitudinal studies of dementia patients indicate an inverted U-shaped curve regarding elevations in systemic blood pressure (Hajjar et al., 2005) • Untreated hypertension during middle age may lead to white matter lesions by promoting atherosclerotic plaques of blood vessel walls thus reducing vessel diameter (Trenkwalder, 2002).

16. With older age continued cerebral hypoperfusion results in protein synthesis defects that lead to classic Alzheimer’s disease markers, i.e. formation of excess β-amyloid plaques and neurofibrillary tangles (de la Torre, 2006)

17. Desired Characteristics of an Anti-dementia Drug • Facilitate cerebral blood flow. • Facilitate cognitive processing, especially memory consolidation and retrieval. • Act separate from the brain cholinergic system.

18. Nle1-Ang IV Nle Tyr Ile His Pro Phe Structures of AngIV and Nle1-Ang IV Angiotensin IV Val Tyr Ile His Pro Phe

19. Morris Water Maze task of Spatial Memory

21. Cognitive Facilitation • Use of the AT4 receptor agonist: Nle1-Angiotensin IV • Has been tested with several animal models of Alzheimer’s disease including: • Perforant path knife-cuts • Cholinergic disruption with scopolamine injections

22. Perforant Path knife-cuts Knife-cut Control

23. Morris water maze perforant path cuts Control group Tmt group

24. Water maze search patterns N Control group PP Cut: aCSF Day 8 61 sec PP Cut: aCSF Day 1 92 sec W E S Tmt group PP Cut: Norleu Day 1 104 sec PP Cut: Norleu Day 8 18 sec

25. Nle1-Ang IV Nle Tyr Ile His Pro Phe Pentapeptide Nle Tyr Ile His Pro Tetrapeptide Nle Tyr Ile His Tripeptide Nle Tyr Ile Structures of Nle1-Ang IV, Pentapeptide, Tetrapeptide, Tripeptide, and Dipeptide Dipeptide Nle Tyr

26. Pretreatment with Scopolaminefollowed by shortened AngIV analogs dipeptide Latency to find platform (sec) tripeptide tetrapeptide pentapeptide Acquisition (days)

27. A Solution for Cognition • First in class treatment approach for dementias. • Lead compounds PNB-0401, PNB-0301, and PNB-0302 are small molecule drugs that can improve memory dysfunction in the scopolamine pretreated rat model of Alzheimer’s disease. • These compounds are designed to penetrate the blood-brain-barrier.

28. Scopolamine followed by tetrapeptide or tripeptide Latency to find platfrom (sec) tetrapeptide tripeptides Acquisition (days)

29. Conclusions • There is presently no adequate treatment for Alzheimer’s dementia. • AT4 receptor agonists promote memory acquisition. • Our current lead compounds are capable of overcoming scopolamine-induced spatial memory impairment and are designed to penetrate the BBB.

31. Ways to Improve Your Memory • Eat healthy foods • Exercise: walk, swim, bike ride, organized exercise programs, etc. • Get enough sleep on a regular schedule • Decrease self-medication: caffeine, alcohol, nicotine. • Reduce multi-tasking • Try to reduce your stress level.

32. Be Motivated to Remember • Make a decision concerning whether you want to memorize something or not. • If you decide to remember a name, face, fact, phone number, then optimize your chances. • Do not hurry! • Get the details correct • Use trigger words or images