Oral cancer pain is debilitating and a significant clinical challenge, in part because even the most efficacious of the currently available remedies are limited by side effects. While chemotherapy and radiotherapy prolong survival, chronic cancer pain creates a poor quality of life. In addition to their respiratory, gastrointestinal and central nervous system (CNS) side effects, the standard of care opioid analgesics have limited long-term effectiveness, due to development of tolerance, dependence, and opioid-induced hyperalgesia, with consequent dose escalations often leading to abuse of prescription opioids. Thus, there is a clear unmet need for more efficacious treatments for cancer pain that will possess favorable therapeutic/side effect profile ratios and in particular lack the CNS side effects and the abuse potential of current clinical opioid medications. We have developed synthetic peripherally-restricted cannabinoid (PRCB) analgesics that offer an alternative approach to the treatment of chronic pain. These compounds target the CB1 receptor, they don't cross the blood-brain barrier, and we have already demonstrated their effectiveness in several pre-clinical models of cancer- and chemotherapy-induced chronic pain, all with a virtual lack of CNS-mediated side effects and tolerance development. Here we propose a milestone-driven progression plan of SAR-informed scaffold-based synthesis, in vitro/in vivo screening, and IND enabling studies for the development of an optimized PRCB for cancer pain treatment. Specific Aim (SA) 1 uses an iterative synthetic approach together with high-throughput in vitro screens that assess target activity, peripheral selectivity, and metabolic stability to discover new PRCB analogs with optimized drug properties. SA2 utilizes industry-standard in vitro assays to assess solubility, protein binding, potential cell toxicity, hepatic enzyme induction, and off-target activity to further inform PRCB optimization. SA3 profiles the in vivo oral cancer pain suppression, CNS side effects, pharmacokinetics, pharmacodynamic target engagement biomarkers, addiction liability, toxicology, and safety pharmacology of the most promising PRCBs. The best candidate to emerge from these studies will then advance in SA4 to full scale-up and IND-enabling studies by NIH CROs, followed by IND application and approval. These studies are prerequisite to the conduct of first-in-man Phase I, single group, double-blind, placebo-controlled, dose-escalation trial of optimal PRCB for oral cancer pain in order to determine its safety, PK, PD and dose-effect, and to confirm target engagement.