Substances addressing the opioid system are widely used pharmaceuticals;agonists (narcotic analgesics) for the treatment of chronic pain;antagonists generally for the treatment of addictive disorders, including substance abuse (opiate, alcohol, amphetamine) and non-substance, i.e. behavioral addictions. Given the difficulties associated with opioid agonist therapy, high risk of death due to overdose (more victims were reported in 2008, than overdose of heroin and cocaine combined) and the development of tolerance and addiction, there is a need for safer narcotic analgesics. The proposed research program uses structural, computational, biophysical, biochemical, and pharmacological approaches: (1) to develop a new level of understanding of the action the opioid receptors, | j , 6, K, and the nociceptin receptor, defining the structural basis for molecuar recognition and activation, and (2) to design new binding ligands.
Aims are to (1) understand opioid receptor molecular recognition and functional selectivity using X-ray crystallography and NMR;(2) understand the molecular mechanisms for functional and pharmacological selectivity for the four receptors using computational approaches;and (3) understand ligand-directed signaling (G-protein-, arrestin-, JNK-dependent) and its relevance in mediating opioid receptor action. Three projects supported by four core groups via inter-project collaborations will address important but difficult questions at a scale not imagined prior to this year. Project 1 will carry ut structural determination on ligand bound complexes. Project 2 will carry out computational studies to define the binding pockets of opioid receptors and perform computer-assisted SBDD to design a new series of optimized compounds including allosteric, functionally selective and bitopic ligands. Project 3, will carry out in vitro and in vivo studies to characterize pharmacological properties of ligands and generate new receptor biased mutants to test hypotheses related to functional selectivity and opioid receptor actions. Core groups support the aims of all 3 projects and will be responsible for (1) large-scale production of purified opioid receptors;(2) synthesis of opiate ligands including newly designed tool compounds for structural and functional studies;(3) molecular profiling and screening of new small molecules, and (4) management and administration of the overall program. Facility resources will be provided by the NIGMS GPCR Networks'Structural Determination Pipeline for large-scale protein production and structure solution and the NIMH Psychoactive Drug Screening Program resources for selectivity profiling of novel small molecules.

Public Health Relevance

Understanding the binding landscape of opioid receptors is essential in attempts at developing new therapeutics needed to address the growing problem of prescription drug addiction as well as at producing highly selective drugs for the 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 #
8667564
Study Section
Special Emphasis Panel (ZRG1-BCMB-S (40))
Program Officer
Rapaka, Rao
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$1,531,889
Indirect Cost
$513,301
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Manglik, Aashish; Lin, Henry; Aryal, Dipendra K et al. (2016) Structure-based discovery of opioid analgesics with reduced side effects. Nature 537:185-190
Bruchas, Michael R; Roth, Bryan L (2016) New Technologies for Elucidating Opioid Receptor Function. Trends Pharmacol Sci 37:279-89
White, Thomas A; Barty, Anton; Liu, Wei et al. (2016) Serial femtosecond crystallography datasets from G protein-coupled receptors. Sci Data 3:160057
Roth, Bryan L (2016) DREADDs for Neuroscientists. Neuron 89:683-94
Kuhar, Jamie Rose; Bedini, Andrea; Melief, Erica J et al. (2015) Mu opioid receptor stimulation activates c-Jun N-terminal kinase 2 by distinct arrestin-dependent and independent mechanisms. Cell Signal 27:1799-806
Vardy, Eyal; Robinson, J Elliott; Li, Chia et al. (2015) A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior. Neuron 86:936-46
O'Connor, Casey; White, Kate L; Doncescu, Nathalie et al. (2015) NMR structure and dynamics of the agonist dynorphin peptide bound to the human kappa opioid receptor. Proc Natl Acad Sci U S A 112:11852-7
Vardy, Eyal; Sassano, Maria F; Rennekamp, Andrew J et al. (2015) Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides. Chem Biol 22:764-75
Isberg, Vignir; de Graaf, Chris; Bortolato, Andrea et al. (2015) Generic GPCR residue numbers - aligning topology maps while minding the gaps. Trends Pharmacol Sci 36:22-31
Robinson, J Elliott; Vardy, Eyal; DiBerto, Jeffrey F et al. (2015) Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism. Neuropsychopharmacology 40:2614-22

Showing the most recent 10 out of 15 publications