The ongoing opioid epidemic has led to the premature death of approximately 500,000 people in the United States from 1999 to 2019. The cyclic tetrapeptide <i>cyclo</i>[Pro-Sar-Phe-D-Phe] acts as a mixed agonist/antagonist of the mu and kappa opioid receptors, and it is a promising lead compound for pain and substance-abuse treatment. To better understand the structure-activity relationship of this molecular scaffold, we performed chemical synthesis, conformational analysis, and in vivo opioid testing of a related cyclic tetrapeptide. Following synthesis, two-dimensional NMR experiments (TOCSY, HSQC, and NOESY) were used to determine the analog’s molecular features, including: dihedral angles, extent of intramolecular hydrogen bonding, and spatial proximity of hydrogen atoms. Molecular modeling was then used to construct and determine all plausible conformations of the analog, and the NMR data were used to identify a likely solution-phase conformation of the analog in chloroform. The conformation of this analog was also determined in the solid state via X-ray crystallography. Finally, the opioid agonist and antagonist activity of the analog was measured using the mouse warm-water tail-withdrawal assay. Major findings will be discussed herein.

Structure-activity relationship of an analog of the opioid cyclic tetrapeptide <i>cyclo</i>[Pro-Sar-Phe-D-Phe]

ACS Spring 2022

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Structure-activity relationship of an analog of the opioid cyclic tetrapeptide cyclo[Pro-Sar-Phe-D-Phe]