Development of Next-generation Pharmacotherapy for Opioid Use Disorders - ABSTRACT:
This application in response to RFA-DA-19-002 proposes a phased plan that will fast track the IND
development of a next-generation medication for opioid use disorders (OUD). The small-molecule compounds
proposed for development are targeted to the nociceptin opioid receptor (NOP) and have shown promising
efficacy in reducing oxycodone intake in nonhuman primates (rhesus monkeys) trained to self-administer
oxycodone with efficacies similar to that of buprenorphine. But unlike buprenorphine, the NOP-targeted
agonist lead compounds show no reinforcing effects by themselves, in monkeys. Also unlike buprenorphine
and methadone, currently used for treating OUDs, NOP-targeted lead compounds do not produce physical
dependence, tolerance, or respiratory depression, upon repeated administration. For the non-medical
prescription opioid addiction, methadone and buprenorphine, both approved for illicit opioid (heroin) addiction
treatment, are used. However, methadone, a mu opioid receptor (MOP) full agonist has significant abuse
liability and causes withdrawal after chronic use, reliance on methadone clinics, and risk of drug overdose-
induced respiratory depression. Buprenorphine (Bup), a MOP partial agonist and kappa opioid receptor (KOP)
antagonist, produces limited respiratory depression; however, clinical studies indicate that it is less effective
than methadone in reducing drug use, craving and relapse. Agonists targeted to the nociceptin/orphanin FQ
peptide (NOP) receptor, the fourth opioid receptor subtype, modulate the pharmacology of MOP agonists and
opioids, particularly in pain and reward circuitries. Our preliminary data shows that small-molecule NOP
agonists reduce morphine-induced reward in rodents and this is further confirmed in our preliminary data in
nonhuman primates, demonstrating promising anti-rewarding properties of a NOP/MOP partial agonist in
decreasing oxycodone self-administration without producing dependence or respiratory depression. Together
our data thus far suggests that the NOP agonists are a promising new approach to treat illicit and
prescription opioid use disorders and may offer an alternative to buprenorphine use.
In the UG3 phase of this project, we propose to conduct non-GLP ADME-tox and efficacy confirmation,
and additional lead optimization if warranted, with the goal/milestone being the nomination of a `IND
candidate' and backup candidates, for IND-enabling studies and an IND filing (in the UH3phase).
