2. Academic Validation
  3. Novel Cyclic Biphalin Analogues by Ruthenium-Catalyzed Ring Closing Metathesis: in Vivo and in Vitro Biological Profile

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

  • ACS Med Chem Lett. 2019 Mar 8;10(4):450-456. doi: 10.1021/acsmedchemlett.8b00495.
Azzurra Stefanucci 1,  Wei Lei 2,  Stefano Pieretti 3,  Marilisa Pia Dimmito 1,  Grazia Luisi 1,  Ettore Novellino 4,  Michał Nowakowski 5,  Wiktor Koźmiński 5,  Sako Mirzaie 6,  Gokhan Zengin 7,  John M Streicher 2,  Adriano Mollica 1
Affiliations

Affiliations

  • 1 Dipartimento di Farmacia, Università di Chieti-Pescara "G. d'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
  • 2 Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85721, United States.
  • 3 Istituto Superiore di Sanità, Centro Nazionale Ricerca e Valutazione Preclinica e Clinica dei Farmaci, Viale Regina Elena 299, 00161 Rome, Italy.
  • 4 Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Naples, Italy.
  • 5 Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland.
  • 6 Department of Biochemistry, Islamic Azad University, Sanandaj, Iran.
  • 7 Department of Biology, Science Faculty, Selcuk University, Konya, Turkey.
PMID: 30996778 DOI: 10.1021/acsmedchemlett.8b00495
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.

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