Science, Serendipity and New Discoveries

Jay Wright and Joe Harding

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

Conversion steps for AngII to AngIII to AngIV

Arg Val Tyr Ile ValHis PhePro LeuHis ThrHisIleAsp Glu

Arg Val Tyr Ile His PhePro LeuHisAsp

Arg Val Tyr Ile His PheProAsp

Arg Val Tyr Ile His PhePro

Val Tyr Ile His PhePro

Angiotensinogen

Angiotensin I

Angiotensin II

Angiotensin III

Angiotensin IV

Renin

ACE

AmA

AmB

Binds to AT1 & AT2:Blood pressureThirstSexual behavior

Binds to AT4:CognitionAngiogenesisCardiac Structure

Wright & Harding, Progress in Neurobiology 2004, 72:263-293

Autoradiogram of AT4 Receptor Subtype Locations in Human Neocortex and Hippocampus

Chai et al., J. Chem Neuroanat 2000, 20:339-348.

AT4 Receptor Subtype Binding in Neocortex and Hippocampus

Categories of Memory

Sensory Memory (a few seconds in duration)

●

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.)

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 of executive function (i.e.

abstract thinking, monitoring complex behaviors)

Diagnostic and Statistical Manual of Mental Disorders IV, 2000 APA

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.)

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

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

Causes of Dementia

Dementia is presently thought to be initiated early in life due to risk factors such as:Elevations in blood pressure Insulin resistanceHypercholesterolemiaCerebrovascular disease

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).

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)

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.

Structures of AngIV and Nle1-Ang IV

Val PheTyr Ile His ProAngiotensin IV

Nle1-Ang IV Nle PheTyr Ile His Pro

Morris Water Maze task Morris Water Maze task of Spatial Memoryof Spatial Memory

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-cutsCholinergic disruption with scopolamine

injections

Perforant Path knife-cuts

Knife-cut Control

Morris water maze perforant path cuts

0

30

60

90

120

Acquisition (days)

Mea

n L

aten

cy t

o F

ind

Ped

esta

l (se

c)PP/aCSFPP/Nle1-AngIVCor/aCSFCor/Nle-AngIV

Control group

Tmt group

Water maze search patterns

PP Cut:

aCSF

Day 1

92 sec

N

S

W E

PP Cut:

aCSF

Day 8

61 sec

PP Cut:

Norleu

Day 1

104 sec

PP Cut:

Norleu

Day 8

18 sec

Control group

Tmt group

Structures of Nle1-Ang IV, Pentapeptide, Tetrapeptide, Tripeptide, and Dipeptide

Nle1-Ang IV Nle PheTyr Ile His Pro

Tripeptide

Nle

Pentapeptide ProHis

His

IleNle

Tetrapeptide

Nle Tyr Ile

IleTyr

Tyr

Nle TyrDipeptide

Pretreatment with Scopolaminefollowed by shortened AngIV analogs

0 2 4 6 80

30

60

90

120

Scop>Nle1-Di (0723)Scop>Nle1-Tri (0722)Scop>Nle1-Tetra (0721)Scop>Nle1-Penta (0720)Scop>Nle1-AngIV (0719)

Lat

en

cy to

fin

d p

latfo

rm (

sec)

Acquisition (days)

tetrapeptidetripeptide

dipeptide

pentapeptide

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.

Scopolamine followed by tetrapeptide or tripeptide

0

30

60

90

120

2 4 6 8

Scop/PNB-0401Scop/PNB-0301Scop/PNB-0302

Acquisition (days)

Late

ncy

to f

ind

plat

from

(se

c)

tetrapeptide

tripeptides

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.

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.

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 correctUse trigger words or images