Corticotrophin releasing factor(CRF) has been implicated in cognitive function and neurological illness such as Alzheimer's disease (AD). Evidence includes large decreases in CRF and up-regulation of CRF receptors in brain areas affected in AD. The benefits of postsynaptic CRF agonist therapy may be outweighed by the anxiogenic side effects of CRF. A membrane associated CRF binding protein with a high affinity for CRF and an ability to inactivate CRF has been identified in brain areas associated with AD. Antagonists of CRF-BP may offer a novel means of increasing synaptic CRF in selective brain areas without the side effects that would occur with a postsynaptic receptor agonist. The proposed studies quantify CRF and CRF-BP in postmortem brain samples in AD and age-matched controls; evaluate the cognitive enhancing effects of CRF-BP in animal models of learning, memory and anxiety; and identify non-peptide leads at the human CRF-BP. The second phase of the proposal will involve optimization of the small molecule CRF-BP leads through a directed chemical synthesis program in order to identify novel orally active drugs for cognitive and neuronal deficits seen in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44NS033426-02A1
Application #
2037845
Study Section
Special Emphasis Panel (ZRG1-NEUA (01))
Program Officer
Oliver, Eugene J
Project Start
1997-03-01
Project End
1999-02-28
Budget Start
1997-03-01
Budget End
1998-02-28
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Neurocrine Biosciences, Inc.
Department
Type
DUNS #
800981276
City
San Diego
State
CA
Country
United States
Zip Code
92130
Zorrilla, Eric P; Schulteis, Gery; Ormsby, Amanda et al. (2002) Urocortin shares the memory modulating effects of corticotropin-releasing factor (CRF): mediation by CRF1 receptors. Brain Res 952:200-10
Zorrilla, E P; Schulteis, G; Ling, N et al. (2001) Performance-enhancing effects of CRF-BP ligand inhibitors. Neuroreport 12:1231-4