Method Development and Pharmacokinetic Study of JY08, A Dual Opioid-NPFF Receptor Ligand

Within the United States and worldwide, a rapidly developing public health crisis is at hand due to the abuse of opioids. With high percentages of Americans experiencing both acute and chronic pain and limited treatment routes, opioid analgesics are highly prescribed in clinical practice. These drugs act on central nervous system to activate opioid receptors in regions of the brain regulating pain and reward. However, these compounds are associated with many unwanted adverse effects including tolerance, dependence, hyperalgesia, and addiction. Thus, there is a need to for the development of new drug candidates that can serve as analgesics for long-term use without the unwanted side effects. The neuropeptide FF (NPFF) system is known to modulate the anti-nociceptive properties of the opioid system. With this knowledge, the development of compounds that can serve both as a NPFF receptor antagonist and an opioid receptor agonist has become a recent focus in analgesic drug discovery and development. The novel compound JY08 was designed as a dual-activity ligand that acts as an agonist at the mu-opioid receptor and antagonist at the NPFF receptor in order to combat the tolerance and hyperalgesia conditions commonly associated with long-term opioid use. Ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) bioanalytical methods were developed for the quantification of JY08 through pharmacokinetic, solubility, and metabolic stability studies