Synthesis and Characterisation of Opioid Receptor (KOR) Antagonists

The opioid crisis was responsible for roughly 60,000 deaths in the United States during 2017, and it has been declared a national health emergency by the White House. Compounds that antagonise the κ opioid receptor have shown utility in the conditioned place preference (CPP) assay, a mouse model of drug-seeking behaviour. The cyclic peptide JVA-4001 shows initial /receptor agonism followed by prolonged receptor antagonism, making it a promising lead compound for treating drug abuse. In this study, we report the synthesis and characterisation of several JVA-4001 analogs—each varying in the identity of one amino acid residue—in order to better understand the unique activity of this molecular scaffold. Solid-phase peptide synthesis was utilised to obtain each analog’s linear precursor, which was confirmed by mass spectroscopy (MS) and high performance liquid chromatography (HPLC). The linear peptides were subsequently cyclised under dilute conditions and characterised using the same protocol. The cyclic peptides were purified using flash chromatography, and their 3D structure will be characterised using CD and NMR in future work