Project Summary Currently, opioid-use disorders are mitigated by replacing illicit opioids with prescription opioids, like methadone and buprenorphine. While this may work for some patients, few patients successfully reach opioid-abstinence. Thus, new agents targeting opioid-use disorders via non- opioid approaches are overdue. One-way opioids induce such tolerance and dependence is through a secondary messenger, cAMP. This signaling molecule reinforces the use of opioids on a biochemical level. This pathway can be altered by an increase of cAMP, by preventing the breakdown of cAMP by phosphodiesterases, PDE. Neuroinflammation is also attenuated by the inhibition of PDE and increased cAMP. On a biological level, chronic opioid-use causes neuroinflammation. Morphine causes immune cells in the brain to become pro-inflammatory, while elevated cAMP induces an anti-inflammatory response. Previous phosphodiesterase-4 inhibitors, PDE4 inhibitors, have shown promise in treating substance abuse disorders, like opioid- use disorders, by reducing this neuroinflammation. However, current inhibitors inhibit multiple PDE4s, including the PDE4D subtype that induces significant nausea and vomiting, limiting these inhibitors’ therapeutic utility. Inhibition of the PDE4B subtype non-toxically interferes with the classic feedback loop in substance use disorders. Thus, this proposal aims to advance a lead compound from a selective PDE4B series. The lead compound has shown significant selectivity for PDE4B over PDE4D. When tested in vitro, the series showed potent anti-inflammatory activity. Additionally, the lead compound has a satisfactory pharmacokinetic profile with decent brain penetration, half-life, bioavailability, etc. When tested against other neurological targets, the lead compound had slight activity against 2 receptors, which may mitigate substance abuse disorders and reduce nausea and vomiting. When tested in a self-administration substance abuse model, the lead compound potently reduced the drug seeking behavior, like prior PDE4 inhibitors. This proposal will focus on confirming lack of toxicity and efficacy. For aim 1, the lead will be tested for off-target liabilities, which may be early indicators of toxicities. In aim 2, toxicity within animal models will be assessed, and induction of nausea and vomiting to the leading competitor. Finally, aim 3 will test efficacy in animal models of opioid self-administration and recurrence. The ultimate goal of this proposal will advance a compound with superior therapeutic use for the treatment of opioid-use disorders.