Funded Projects

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: RFA-DA-19-002
Summary:

The expansion of opioid prescribing in recent years to better treat pain has markedly increased their usage and availability and fueled an epidemic of abuse. Up to 80 percent of addicts reported initiating their habit through prescriptions drugs. Decreasing opioid prescriptions would lower opioid exposure, with fewer people receiving the drugs and less drug available for diversion. Study investigators have identified a novel target in the brain, distinct from any of the traditional opioid receptors capable of mediating potent analgesia without the reward behavior and side effects seen with traditional opioids. They targeted this site with a series of arylepoxamides and have identified a clinical candidate (MP1000) and backup compound. MP1000 is a potent analgesic in a range of thermal, inflammatory, and neuropathic analgesic assays. It fails to show reward behavior and does not produce respiratory depression at doses 5-fold greater than its analgesic ED50. Chronic administration does not produce physical dependence or withdrawal when challenged with an antagonist. It shows no cross tolerance to morphine and can be co-administered to subjects already on opioids for pain to lower their opioid usage (i.e., opioid sparing), facilitating the eventual discontinuation of the opioid. If successful, this project could lead to the development of a viable alternative to current opioid-based analgesics with reduced side effects (such as reward and respiratory depression) compared to opioids.

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: RFA-DA-19-002
Summary:

To address the need for novel therapeutics for opioid use disorder (OUD), this research group identified ghrelin as an endogenous regulator of the mesocorticostriatal circuit, which contributes to the enhanced motivational attributes of addictive drugs and drug-associated cues. Ghrelin binds to the growth hormone secretagogue receptor 1? (GHS1?R) to transduce several physiological and behavioral processes, including the reward-related effects of opioid agonists. Systemic administration of a GHS1?R antagonist/inverse agonist dose-dependently attenuated self-administration of the addictive opioid analgesic oxycodone as well as oxycodone-seeking. This project proposes to employ a suite of validated rodent OUD models to define the preclinical profile for PF5190457, a selective GHS1?R antagonist/inverse agonist. PF5190457’s abuse liability, ability to suppress withdrawal and relapse-like behaviors, drug metabolism and pharmacokinetics, and brain penetrability in rats will be assessed. Phase 1 clinical studies in non–treatment seeking OUD participants will follow to assess the safety and tolerability of PF5190457.

NOFO Title: HEAL Initiative: Novel Targets for Opioid Use Disorders and Opioid Overdose (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-DA-22-031
Summary:

This research project will investigate the cannabinoid receptor 2 protein (CB2R) as a novel therapeutic target for opioid-induced respiratory depression caused by fentanyl, oxycodone, and heroin. This study will shed light on how the endocannabinoid system in the brainstem works to control breathing under normal conditions and during opioid-induced respiratory depression. The research aims to determine whether activation of the CB2R with a brain-penetrant CB2R-binding molecule is safe and clinically useful for treating opioid overdose prevention and reversal. This research will pave the way for discovering new medications that activate CB2R to reduce opioid-related deaths.

NOFO Title: HEAL Initiative: Novel Targets for Opioid Use Disorders and Opioid Overdose (R21 Clinical Trial Not Allowed)
NOFO Number: RFA-DA-22-032
Summary:

Safe and effective options are urgently needed to prevent and treat opioid use disorder and polysubstance use disorders. Previous research in humans and animals suggests that activating the calcium-activated potassium channel KCa2.2 is a promising therapeutic approach for treating substance use disorders and associated health conditions. This project will perform a virtual high-throughput screen using novel machine learning approaches to discover new molecules that interact with the KCa2.2 channel. The newly discovered molecules help develop novel drugs for the treatment of opioid use disorder and associated health conditions.

NOFO Title: HEAL Initiative: Novel Targets for Opioid Use Disorders and Opioid Overdose (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-DA-22-031
Summary:

Currently available treatments for opioid use disorder (OUD) are insufficient for many patients. Novel compounds that can promote alterations in brain connections (i.e., neural plasticity) possess enormous potential for improving substance use disorder (SUD) treatments. Psychedelic compounds induce neural plasticity and can elicit long-lasting, beneficial impacts on a wide variety of SUDs. However, these compounds have significant side effects, including hallucinations and cardiotoxicity. Researchers have developed a novel, synthetic derivative of the psychedelic ibogaine, called tabernanthalog, that does not have these side effects. This compound has demonstrated both short- and long-term therapeutic effects in a preclinical model of OUD. This research study will determine the molecular and neural mechanisms through which tabernanthalog affects opioid seeking. It will also evaluate whether the effects are specific to opioids and do not alter response to natural rewards and will examine the efficacy of tabernanthalog in a preclinical model of comorbid opioid and alcohol use disorder.

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: PAR-20-092
Summary:

This project aims to develop a new way to stimulate the delta opioid receptor to treat withdrawal and abstinence from chronic opioid use. Withdrawal can cause pain, depression, and anxiety, which contribute to relapse. The research will test promising drug candidates in animal models with the intention of bringing at least one effective and safe compound to the final stage of drug development before human clinical trials can begin.

NOFO Title: HEAL Initiative: Novel Targets for Opioid Use Disorders and Opioid Overdose (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-DA-22-031
Summary:

Novel treatments for opioid use disorder are urgently needed. Previous research has shown that angiotensin-converting enzyme (ACE) can control levels and activity of natural, “endogenous,” opioids in a way that might reduce the rewarding effects of opioids like fentanyl. ACE inhibitors have been used to treat hypertension for decades, with no evidence of addiction or dependence. This research will evaluate ACE effects on endogenous opioids toward generating new, domain-specific ACE inhibitors with optimized properties for treating opioid use disorder. The research will also test the behavioral impact of these compounds in preclinical models of opioid use disorder. 

NOFO Title: Device-Based Treatments for Substance Use Disorders (UG3/UH3, Clinical Trial Optional)
NOFO Number: PAR-18-494

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: RFA-DA-19-002
Summary:

Extended-release naltrexone (XR-NTX) reduces overdose risk; however, transitioning to XR-NTX requires detoxification, which is a major hurdle. Non-opioid detoxification with an alpha-2 adrenergic receptor agonist, such as lofexidine, may shorten detoxification time, but it does not reduce the subjective effects of withdrawal. Pregabalin potentiates the activity of glutamic acid decarboxylase, inhibits calcium influx and release of excitatory neurotransmitters, raises GABA levels, and is approved for neuropathic pain, for fibromyalgia, and as an adjunctive therapy for adults with partial onset seizures. The study will test whether pregabalin can be combined with lofexidine to better reduce the subjective effects of opioid withdrawal than lofexidine alone and increase the proportion of patients that transition to XR-NTX. Such a dosing combination could lower the detoxification hurdle for patients who are interested in antagonist treatment or who are in settings where it is unavailable or difficult to access.

NOFO Title: NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
NOFO Number: PA-18-484
Summary:

Opioids remain the gold standard for treating moderate to severe pain, but their use is limited by numerous adverse effects, including tolerance, dependence, abuse, and overdose. Adverse effects could be avoided by combining an opioid with another drug, such that smaller doses of the opioid (in combination with another drug) produce the desired therapeutic effect. Direct-acting serotonin type 2 (5-HT2) receptor agonists interact in a synergistic manner with the opioid morphine to produce antinociceptive effects, suggesting a 5-HT2 receptor agonist could be combined with small amounts of an opioid to treat pain, thereby lowering the risk associated with larger doses. Unfortunately, very little is known about interactions between 5-HT2 receptor agonists and other opioids. The proposed studies will evaluate the therapeutic potential of mixtures of opioids and 5-HT2 receptor agonists using highly translatable and well-established procedures to characterize the antinociceptive, respiratory-depressant (overdose), positive-reinforcing (leading to misuse), and discriminative-stimulus (subjective) effects of drug mixtures as well as the impact of chronic treatment on the development of tolerance to and physical dependence on opioids. If successful, these studies will provide proof-of-concept for this innovative approach to pain treatment and evaluate the utility of targeting 5-HT receptors for analgesic drug development.

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: RFA-DA-19-002
Summary:

Medication-based treatment for opioid use disorder OUD aids in reducing mortality, opioid withdrawal, intake and opioid-seeking behaviors, however there is a clear need to increase the armamentarium of therapeutics for OUD. The ?non-classical? NOcicePtin receptor (NOPr) binds the endogenous neuropeptide nociceptin/orphanin FQ (N/OFQ) and is a promising target based on the evidence for its function in the regulation of the rewarding and motivational effects of opioids and alcohol. This study plans to assess the ability of the novel and selective NOPr antagonist BTRX-246040 to block oxycodone intake without abuse liability, and to suppress oxycodone withdrawal and relapse-like behaviors in rats. The study will also determine Drug Metabolism and Pharmacokinetics interactions (DMPK) between oxycodone and BTRX-246040 and brain penetrability in male and female rats. If successful, these preclinical studies will be followed by a Phase 1 clinical trial in non-treatment seeking OUD participants. These investigations will advance the prospects of validating a novel medication for OUD.

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: PAR-20-092
Summary:

The nation’s opioid epidemic remains a public health emergency, marked by high rates of opioid use and misuse among adults and a correlated rising incidence of neonatal opioid withdrawal syndrome (NOWS) in infants exposed to opioids before they are born. There are currently no pharmacotherapies approved by the Food and Drug Administration (FDA) for the treatment of NOWS. This research will complete manufacturing and clinical trial activities to evaluate and support FDA approval of a pediatric-appropriate formulation of lofexidine, a non-opioid medication approved for mitigation of opioid withdrawal symptoms in adults, as a first line-therapy in NOWS patients through two clinical trials to (1) identify an optimal dosing regimen of lofexidine for treatment of NOWS, and (2) evaluate the risks and benefits of its use in improving withdrawal symptoms, limiting infant exposure to other off-label narcotic medications and shortening the infant’s overall stay in the hospital.

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: RFA-DA-19-002
Summary:

There is a need to develop a mu-opioid receptor (MOR) treatment with enhanced therapeutic effects and reduced undesirable effects. Recently, several highly selective and potent MOR modulators have been identified as novel leads for opioid use disorder treatment. They all showed more promising pharmacological profiles compared to other known drugs in this category. The current proposal will focus on further development of these leads for preclinical IND-enabling studies and dynamic drug discovery and development pipeline construction. This project plans to further validate therapeutic profiles of the current leads with self-administration and pharmacokinetic studies and expand the small-molecule library to build a dynamic drug discovery and development pipeline. Preclinical IND-enabling studies on the identified lead(s) will be conducted, and in vivo pharmacokinetics and pharmacodynamics profiles of the new hits will be compared with current leads to define the next generation of lead compound(s).