Design, Synthesis, and Characterization of the Macrocyclic Tetrapeptide cyclo[Pro-Sar-Phe- d -Phe]: A Mixed Opioid Receptor Agonist-Antagonist following Oral Administration

Michael J. Ferracane, Ariana C. Brice-Tutt, Jeremy S. Coleman, Grant G. Simpson, Lisa L. Wilson, Shainnel O. Eans, Heather M. Stacy, Thomas F. Murray, Jay P. McLaughlin, Jane V. Aldrich

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1324-1336
Number of pages13
JournalACS Chemical Neuroscience
Volume11
Issue number9
DOIs
StatePublished - May 6 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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    Ferracane, M. J., Brice-Tutt, A. C., Coleman, J. S., Simpson, G. G., Wilson, L. L., Eans, S. O., Stacy, H. M., Murray, T. F., McLaughlin, J. P., & Aldrich, J. V. (2020). Design, Synthesis, and Characterization of the Macrocyclic Tetrapeptide cyclo[Pro-Sar-Phe- d -Phe]: A Mixed Opioid Receptor Agonist-Antagonist following Oral Administration. ACS Chemical Neuroscience, 11(9), 1324-1336. https://doi.org/10.1021/acschemneuro.0c00086