The overall and specific goal of this application is the identification of novel high affinity and selective functional agonists of the nociceptin receptor that can be used to treat cocaine addiction. In previous efforts, we have identified, designed and synthesized novel, potent, and selective nociceptin receptor (a.k.a. ORL-1, NOP) agonists as tools for research on substance dependence with potential as clinically effective therapeutic agents. The disease target, cocaine abuse, represents an enormous health burden on society and for which currently available pharmacotherapies have insufficient efficacy. We propose nociceptin receptor agonism as a mechanism to achieve the therapeutic objective. Studies suggest that nociceptin activation opposes the dependence effects of substances of abuse such as nicotine, alcohol and cocaine. We propose nociceptin receptor activation as a mechanism to achieve the therapeutic objective of reduced cocaine addiction. While no clinical validation exists for the mechanism, the hypothesis supported by preclinical data, and would benefit from directed studies using optimized ligands, such as those we propose, to uncover the contributions of the nociceptin receptor to cocaine abuse as the first steps in developing novel therapeutics. In this application, we extend this molecule development program to center on the design, synthesis and evaluation of agents for that can be used in cocaine addiction research with potential to become therapeutics based on their actions at the nociceptin receptor. The pharmacology of novel compounds will be assessed in multiple cell-based assays and will include opioid receptor counterscreens to routinely determine potency and selectivity at a very early stage. The compound starting points for this project show no addictive potential, and a high level of selectivity over the mu opioid receptor, an improvement over currentiy available NOP agonists. This application is aimed at the development of the idea that nociceptin receptor agonists can be used to treat cocaine abuse.

Public Health Relevance

Cocaine use represents an enormous worldwide health burden, in the US alone in 2009 more than 4.8 million people abused cocaine. Current cocaine use therapies are simply not effective and novel therapeutics are greatly needed. This project will test the hypothesis that the nociceptin receptor is involved in cocaine reward pathways in an attempt to validate the nociceptin receptor as a target for novel therapeutics to treat cocaine abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA035055-03
Application #
8652971
Study Section
Special Emphasis Panel (ZDA1)
Program Officer
Acri, Jane
Project Start
2012-06-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Swords, Ronan T; Azzam, Diana; Al-Ali, Hassan et al. (2018) Ex-vivo sensitivity profiling to guide clinical decision making in acute myeloid leukemia: A pilot study. Leuk Res 64:34-41
Lohse, Ines; Al-Ali, Hassan; Volmar, Claude-Henry et al. (2018) Ex vivo drug sensitivity testing as a means for drug repurposing in esophageal adenocarcinoma. PLoS One 13:e0203173
Mustafi, Sushmita; Camarena, Vladimir; Volmar, Claude-Henry et al. (2018) Vitamin C Sensitizes Melanoma to BET Inhibitors. Cancer Res 78:572-583
Volmar, Claude-Henry; Salah-Uddin, Hasib; Janczura, Karolina J et al. (2017) M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing Alzheimer's disease genes and improving memory. Proc Natl Acad Sci U S A 114:E9135-E9144
Jones, Candace; Barrera, Ingrid; Brothers, Shaun et al. (2017) Oxytocin and social functioning. Dialogues Clin Neurosci 19:193-201
Wahlestedt, Claes (2017) Emerging Epigenetic Therapies in Neuroscience: Focus on Bromodomain-Containing Drug Targets. Neuropsychopharmacology 42:374
Aziz, Abdul Maruf Asif; Brothers, Shaun; Sartor, Gregory et al. (2016) The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models. Psychopharmacology (Berl) 233:3553-63
Sartor, G C; Powell, S K; Wiedner, H J et al. (2016) Nociceptin receptor activation does not alter acquisition, expression, extinction and reinstatement of conditioned cocaine preference in mice. Brain Res 1632:34-41
Sartor, Gregory C; Powell, Samuel K; Brothers, Shaun P et al. (2015) Epigenetic Readers of Lysine Acetylation Regulate Cocaine-Induced Plasticity. J Neurosci 35:15062-72
Andero, RaĆ¼l; Brothers, Shaun P; Jovanovic, Tanja et al. (2013) Amygdala-dependent fear is regulated by Oprl1 in mice and humans with PTSD. Sci Transl Med 5:188ra73