Posttraumatic stress disorder (PTSD) is a highly distressing and potentially disabling condition involving altered fear learning that occurs in some individuals after exposure to highly traumatic events. While generic antidepressants and short-term anxiolytics are the mainstays of PTSD treatment, these drugs remain insufficient to treat the disease. Thus, there remains a large unmet medical need to develop novel therapies for PTSD and other fear related disorders. In our previously published work, in a cohort of 1847 human PTSD patients with a history of significant lifetime trauma, we found that a single-nucleotide polymorphism (SNP) within the gene encoding the nociceptin receptor (NOP-R) is associated with increased PTSD symptoms. We also found that this SNP is associated with fear generalization and increased amygdala-insula functional connectivity. Using a mouse model of dysregulated fear, we found altered expression of the oprl1 gene (encoding NOP-R) within the amygdala. Systemic and central amygdala infusion of SR-8993, our highly selective NOP-R agonist, impaired fear memory consolidation, suggesting that NOP-R is associated with fear processing and PTSD symptoms. Our data also suggest that activation of the NOP-R interferes with fear memory consolidation, with implications for the treatment of PTSD even after a traumatic event. The specific goal of this project is to develop useful NOP-R modulators to understand the biology of the NOP-R with a view toward eventual clinical application. The compounds we developed in previous efforts, and their analogs, are best-suited to reach this goal due to unprecedented selectivity for the NOP-R over the other opioid receptors, particularly the mu opioid receptor (MOR). Selectivity for NOP-R over the mu receptor is necessary to reduce addiction potential and avoid the unwanted side effects that are associated with MOR activation, including respiratory depression, constipation and itch/pruritus. However, our published lead compound, SR-8993, with some selectivity for NOP-R over MOR, continues to have significant MOR agonist activity, one feature that we aim to correct in this proposed work. In support of the feasibility of our approach, we show unpublished compounds that have over 10,000-fold selectivity for NOP-R over MOR. Additional chemistry efforts will be aimed at improving the drug-like characteristics of preferred leads and to improve pharmacokinetic (PK) properties (Aim 1). Pharmacological profiling will include assessments of NOP-R and opioid receptor function with further assessments of DMPK parameters to ensure the potential for in vivo utility (Aim 2). PTSD-like animal models will be used to assess target-exposure relationships, and a battery of in vivo neuro-behavioral and also addiction potential assessments will be used to determine potential for undesired effects (Aim 3).
We aim to deliver a set of pre-clinically validated, safe, highly selective, brain penetrant small molecule nociceptin receptor agonists that attenuate PTSD-like fear and anxiety behavior in well-validated PTSD models that are primed for clinical translation.

Public Health Relevance

Posttraumatic stress disorder (PTSD) is a debilitating condition that can arise after exposure to highly traumatic events. We identified the nociceptin receptor as potentially playing a role in human PTSD patients, with its activation ameliorating PTSD-like symptoms in rodent models. We propose to enhance the drug-likeness of our nociceptin receptor agonists for elucidating the potential of NOP-R agonists to treat PTSD, with a view toward clinical utilization for treatment and potentially prevention of PTSD following trauma exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH110441-04
Application #
9688573
Study Section
Drug Discovery for the Nervous System Study Section (DDNS)
Program Officer
Michelotti, Enrique
Project Start
2016-07-21
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2021-04-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
052780918
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
Seldeen, K L; Halley, P G; Volmar, C H et al. (2018) Neuropeptide Y Y2 antagonist treated ovariectomized mice exhibit greater bone mineral density. Neuropeptides 67:45-55
Lohse, Ines; Wildermuth, Erin; Brothers, Shaun P (2018) Naturally occurring compounds as pancreatic cancer therapeutics. Oncotarget 9:35448-35457
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
Maheu, Marissa E; Ressler, Kerry J (2017) Developmental pathway genes and neural plasticity underlying emotional learning and stress-related disorders. Learn Mem 24:492-501
Jones, Candace; Barrera, Ingrid; Brothers, Shaun et al. (2017) Oxytocin and social functioning. Dialogues Clin Neurosci 19:193-201
Volmar, Claude-Henry; Wahlestedt, Claes; Brothers, Shaun P (2017) Orphan diseases: state of the drug discovery art. Wien Med Wochenschr 167:197-204
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