Between 1999-2019, nearly 500,000 Americans died from an overdose involving an opioid. Overdose deaths continue to grow, reaching over 49,000 in 2019. Medications that treat pain or addiction with fewer adverse effects are urgently needed to help stem the opioid overdose epidemic. We recently reported the novel cyclic tetrapeptide cyclo[Pro-Sar-Phe-D-Phe], which possesses mixed mu- and kappa-opioid receptor (MOR & KOR) agonist and KOR antagonist activity in vivo. This peptide demonstrates utility in treating pain without respiratory depression, and it attenuates the rewarding effects of cocaine and morphine in mouse model systems. Notably, cyclo[Pro-Sar-Phe-D-Phe] is both orally bioavailable and blood-brain barrier permeable, properties that are rare for a peptide. Herein, we describe our effort to design, synthesize, and study this peptide as well as a series of initial analogs to better understand the structure-activity relationship of this unique molecular scaffold.

Rational design, synthesis, conformational analysis, and opioid activity of cyclo[Pro-Sar-Phe-D-Phe] and its analogs

ACS Fall 2021

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