TY - JOUR
T1 - Novel Cyclic Biphalin Analogues by Ruthenium-Catalyzed Ring Closing Metathesis
T2 - in Vivo and in Vitro Biological Profile
AU - Stefanucci, Azzurra
AU - Lei, Wei
AU - Pieretti, Stefano
AU - Dimmito, Marilisa Pia
AU - Luisi, Grazia
AU - Novellino, Ettore
AU - Nowakowski, Michał
AU - Koźmiński, Wiktor
AU - Mirzaie, Sako
AU - Zengin, Gokhan
AU - Streicher, John M
AU - Mollica, Adriano
PY - 2019/4/11
Y1 - 2019/4/11
N2 - 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.
AB - 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.
U2 - 10.1021/acsmedchemlett.8b00495
DO - 10.1021/acsmedchemlett.8b00495
M3 - Article
C2 - 30996778
VL - 10
SP - 450
EP - 456
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 4
ER -