Morphine, a mu-opioid receptor (μOR) agonist, is clinically preferred in pain management. However, prolonged morphine use is associated with side effects such as tolerance development, abuse liability, respiratory depression, and itching. Studies suggest that selective kappa-opioid receptor (kOR) agonists biased towards G-protein signaling over β-arrestin recruitment could lead to novel therapeutics for treating intractable itch and pain with reduced side effects. Thus, a key gap and critical need for effective pain management is the development of selective kappa-opioid analgesics with reduced side effects.  Collybolide, a natural product isolated from the mushroom Collybia Maculata has exhibited potent analgesic properties without the side effects seen in well-known analgesics such as morphine, due to its selectivity for the kappa-opioid receptor. This project will focus on the synthesis and evaluation of collybolide analogs. This work will lead to a better understanding of the kappa-opioid receptor pharmacology to develop potential therapeutics for the treatment of pain with reduced addiction hazards.