Novel Cyclic Biphalin Analogues by Ruthenium-Catalyzed Ring Closing Metathesis: in Vivo and in Vitro Biological Profile

Azzurra Stefanucci, Wei Lei, Stefano Pieretti, Marilisa Pia Dimmito, Grazia Luisi, Ettore Novellino, Michał Nowakowski, Wiktor Koźmiński, Sako Mirzaie, Gokhan Zengin, John M Streicher, Adriano Mollica

Research output: Contribution to journalArticlepeer-review

Abstract

In this work we report the application of the ring-closing metathesis (RCM) to the preparation of two cyclic olefin-bridged analogues of biphalin (Tyr-d-Ala-Gly-Phe-NH-NH ← Phe ← Gly ← d-Ala ← Tyr), using the second generation Grubbs' catalyst. The resulting cis- and trans-cyclic isomers were identified, fully characterized, and tested in vitro at μ (ΜΟR), δ (DOR), and κ (KOR) opioid receptors and in vivo for antinociceptive activity. Both were shown to be full agonists at MOR and potential partial antagonists at DOR, with low potency KOR agonism. They also share a strong antinociceptive effect after intracerebroventricular (i.c.v.) and intravenous (i.v.) administration, higher than that of the cyclic biphalin analogues containing a disulfide bridge between the side chains of two d-Cys or d-Pen residues, previously described by our group.

Original languageEnglish
Pages (from-to)450-456
Number of pages7
JournalACS Medicinal Chemistry Letters
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 11 2019

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