The objectives of Project 2 are the refinement and application of G protein-dependent cell-based functional assays for monitoring Orexin 1 receptor (0X1R) activity, suitable to determine potency and mechanism of action of 0X1R antagonists that have the potential to be developed as novel therapeutics for the treatment of nicotine dependence. In addition, a series of G protein-independent cell-based functional assays will be developed and optimized to further characterize 0X1R ligands and allow for identification of compounds exhibiting 'functional selectivity'. Compounds synthesized in Project 1 and compounds emerging from the OXIR high throughput screening (HTS) campaign of the 'Molecular Libraries Probe Production Centers Network'(MLPCN) sample collection will be characterized in the aforementioned assays against recombinant 0X1R in high throughput fashion. Counterscreens to assess selectivity of high priority potent modulators will also be developed and activity of interesting compounds will be confirmed using primary neuronal cells to help bridge the gap between in vitro and in vivo pharmacology. This multiple assay approach together with pharmacokinetic data generated in Project 3 is designed to drive an iterative medicinal chemistry program (Project 1) aimed at identifying potent, selective, cell penetrant 0X1R antagonists that will advance to in vivo efficacy studies in animal models of nicotine dependence (Project 4).

Public Health Relevance

; Nicotine dependence is characterized by high rates of relapse to cigarette smoking during periods of abstinence. Indeed high rates of relapse are considered the greatest obstacle to successfully treating nicotine addiction. Thus, development of novel pharmacotherapeutics that can decrease the vulnerability to relapse and thereby facilitate long-term abstinence is crucial for effective treatment of nicotine dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA033622-03
Application #
8653563
Study Section
Special Emphasis Panel (ZDA1-JXR-D)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$429,783
Indirect Cost
$212,721
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037