With over 2 million people in the United States alone known to abuse opioid-based pain medications, addiction to these drugs represents a significant public health concern. The mu-opioid receptor (MOR) is the member of the G protein-coupled receptor (GPCR) family that primarily mediates the actions of clinically used opioid- based analgesics. Based on extensive in vitro and in vivo work over the past decades, it has become increasingly clear that opioid ligands can produce different signaling, phosphorylation, desensitization, and internalization of MOR, with major implications for its physiological responses, including the development of analgesic tolerance. The recent suggestion that MOR oligomerization can modulate receptor binding, signaling, and/or trafficking further complicates our understanding of MOR-mediated function. The overall goal of the research proposed in this application is to reveal the molecular mechanisms underlying the observed functional selectivity at MOR. This information is important to ensure the fine-tuning of MOR signaling towards desired therapeutic pathways but away from those mediating adverse side effects, with the ultimate goal of discovering non-addictive analgesic agents. The computational research proposed in this grant application takes advantage of cutting-edge developments in theory and experiments to obtain rigorous mechanistic insight, at an unprecedented level of molecular detail, into the structure, spatio-temporal organization, and dynamics of MOR in the membrane, thus broadening current understanding of MOR biased agonism. Specifically, we will contribute structural and dynamic information regarding sparsely-populated states of MOR that are currently impossible or difficult to retrieve experimentally, thereby generating testable hypotheses of how, at the molecular level, different opioids induce differential oligomerization and signaling of MOR, leading to the specific behavioral effects of the drugs. Experimental validation of these computational predictions, to be attained through collaborations with independently funded laboratories, will advance our current understanding of fundamental basic mechanisms of MOR function, and pave the way to novel therapeutic strategies against drug abuse and addiction. The data that will emerge from this application will be added to other relevant recent information on GPCR oligomerization, and further populate our recently deployed GPCR-Oligomerization Knowledge Base system to continue to promote and support productive collaborations between computational and experimental scientists working on GPCRs involved in drug abuse.

Public Health Relevance

The goal of our research is to understand the molecular mechanisms underlying the diverse physiological functions of mu-opioid receptors to ultimately develop analgesics that are free from side effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA034049-01
Application #
8343893
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Hillery, Paul
Project Start
2012-06-15
Project End
2017-05-31
Budget Start
2012-06-15
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$343,238
Indirect Cost
$140,738
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Shang, Yi; Yeatman, Holly R; Provasi, Davide et al. (2016) Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors. ACS Chem Biol 11:1220-9
Crowley, Rachel Saylor; Riley, Andrew P; Sherwood, Alexander M et al. (2016) Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability. J Med Chem 59:11027-11038
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Schneider, Sebastian; Provasi, Davide; Filizola, Marta (2016) How Oliceridine (TRV-130) Binds and Stabilizes a μ-Opioid Receptor Conformational State that Selectively Triggers G Protein-Signaling Pathways. Biochemistry :
Provasi, Davide; Boz, Mustafa Burak; Johnston, Jennifer M et al. (2015) Preferred supramolecular organization and dimer interfaces of opioid receptors from simulated self-association. PLoS Comput Biol 11:e1004148
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Schneider, Sebastian; Provasi, Davide; Filizola, Marta (2015) The Dynamic Process of Drug-GPCR Binding at Either Orthosteric or Allosteric Sites Evaluated by Metadynamics. Methods Mol Biol 1335:277-94
Shang, Yi; Filizola, Marta (2015) Opioid receptors: Structural and mechanistic insights into pharmacology and signaling. Eur J Pharmacol 763:206-13
Ferré, Sergi; Casadó, Vicent; Devi, Lakshmi A et al. (2014) G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacol Rev 66:413-34

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