Substance abuse remains a serious public health crisis, affecting millions of people worldwide. Macrocyclic tetrapeptides like
CJ-15,208 and [d-Trp]
CJ-15,208 demonstrate
opioid activity shown to attenuate the rewarding effects of
cocaine in conditioned place preference assays in mice, making them promising lead compounds for treating
substance abuse. In the present study, we report the rational design, synthesis, conformational analysis, and continued pharmacological evaluation of the novel macrocyclic tetrapeptide cyclo[Pro-Sar-Phe-d-Phe] to further explore this unique molecular scaffold. This
peptide was rationally designed based on X-ray and NMR structures of related macrocyclic tetrapeptides. Following synthesis, its
solution-phase conformations were determined by NMR and molecular modeling. The
peptide adopted multiple conformations in polar
solvents, but a single conformation in
chloroform that is stabilized by intramolecular hydrogen bonding. The
peptide is orally bioavailable, producing antinociception and antagonism of
kappa opioid receptor (KOR) stimulation following
oral administration in a mouse 55 °C warm-water tail-withdrawal assay. Notably, cyclo[Pro-Sar-Phe-d-Phe] blocked both stress- and
drug-induced reinstatement of
cocaine and
morphine conditioned place preference in mice following
oral administration, and displayed a decreased side-effect profile compared to
morphine. Thus, cyclo[Pro-Sar-Phe-d-Phe] is a promising lead compound for the treatment of
substance abuse.