Progress toward synthesis of analogs of a cyclic opioid peptide

HARBESON 41

Opioid drugs have become the cause of an epidemic in the United States, and they are responsible for thousands of overdose deaths. The cyclic opioid peptide CJ-15,208 has shown to be effective in the Conditioned Place Preference (CPP) assay, which models drug seeking behavior in mice. This peptide may be useful for the treatment of addiction, and functions as an antagonist of the kappa opioid receptor. We are interested in synthesizing analogs of CJ-15,208 to determine the scaffold’s structure-activity relationship. First, solid-phase peptide synthesis was performed to obtain the linear precursors of the desired cyclic peptides. To date, two of these linear species have been cyclized to obtain the corresponding cyclic products. All linear and cyclic products have been analyzed via High-Pressure Liquid Chromatography (HPLC) and Liquid Chromatography Mass Spectrometry (LC-MS) to determine their yield and purity. Future work will focus on cyclization of the remaining analogs and purification of all the products by flash chromatography and. Once complete, the analogs will be characterized by Nuclear Magnetic Resonance (NMR) spectroscopy and Circular Dichroism (CD) to determine their 3-D structure and submitted for pharmacological testing to determine their activity in the CPP assay.