TY - JOUR
T1 - Design, Synthesis, and Characterization of the Macrocyclic Tetrapeptide cyclo[Pro-Sar-Phe- d -Phe]
T2 - A Mixed Opioid Receptor Agonist-Antagonist following Oral Administration
AU - Ferracane, Michael J.
AU - Brice-Tutt, Ariana C.
AU - Coleman, Jeremy S.
AU - Simpson, Grant G.
AU - Wilson, Lisa L.
AU - Eans, Shainnel O.
AU - Stacy, Heather M.
AU - Murray, Thomas F.
AU - McLaughlin, Jay P.
AU - Aldrich, Jane V.
N1 - Funding Information:
This research was supported by grants from the National Institute on Drug Abuse R01 DA023924 and the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program under award no. W81XWH-15-1-0452 (to J.V.A.) and W81XWH-15-1-0464 (to J.P.M.). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. High-resolution mass spectra were acquired at the University of Florida Mass Spectrometry Research and Education Center, which is supported by NIH S10 OD021758-01A1.
Funding Information:
This research was supported by grants from the National Institute on Drug Abuse R01 DA023924 and the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program under award no. W81XWH-15-1-0452 (to J.V.A.) and W81XWH-15-1-0464 (to J.P.M.). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. High-resolution mass spectra were acquired at the University of Florida Mass Spectrometry Research and Education Center, which is supported by NIH S10 OD021758-01A1.
Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/5/6
Y1 - 2020/5/6
N2 - 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.
AB - 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.
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U2 - 10.1021/acschemneuro.0c00086
DO - 10.1021/acschemneuro.0c00086
M3 - Article
C2 - 32251585
AN - SCOPUS:85084272591
VL - 11
SP - 1324
EP - 1336
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 9
ER -