Substances addressing the opioid system are widely used pharmaceuticals. Agonists (narcotic analgesics) are used for the treatment of chronic pain, whereas antagonists are generally effective in the treatment of addictive disorders, including substance abuse (opiate, alcohol, amphetamine) and non-substance, i.e. behavioral addictions such as gaming, gambling and over-eating. The proposed program project will use structural, biophysical, biochemical, and pharmacological approaches to understand ligand binding properties of all opioid receptors (p-, 6, K (MOR, DOR, KOR), and the nociceptin/orphanin FQ peptide receptor (NOP)) and to define the structural basis for molecular recognition and activation. The three overall aims are (1): Understand opioid receptor molecular recognition and functional selectivity using X-ray crystallography to determine structures of ligand-receptor complexes and NMR to understand dynamic behavior. (2) Understand the molecular mechanisms for functional and pharmacological selectivity for the four opioid receptors using computational approaches, and (3) Understand ligand-directed signaling (G- protein-, arrestin-, JNK-dependent) and its relevance in mediating opioid receptor action. Management and administration of the project will be carried out by the Management and Administration Core. Its main responsibilities include (1) Overall management of all project to ensure progress, (2) Prioritization of studies, (3) Assembly of a Scientific Advisory Board, (4) Preparation of required progress reports, (5) Establishment and facilitation of communication routes within the POI as well as with external stakeholders (e.g. SAB, NIH), and (6) Assurance ofthe high quality of studies and results.

Public Health Relevance

Understanding the binding landscape of opioid receptors is essential in developing new therapeutics needed to address the growing problem of prescription drug addiction as well as at producing highly selective drugs forthe treatment of wide ranging conditions including pain, anxiety, depression, and physical dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
1P01DA035764-01A1
Application #
8721110
Study Section
Special Emphasis Panel (ZRG1-BCMB-S (40))
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$140,507
Indirect Cost
$62,649
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Katritch, Vsevolod; Fenalti, Gustavo; Abola, Enrique E et al. (2014) Allosteric sodium in class A GPCR signaling. Trends Biochem Sci 39:233-44