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

doi:10.1021/acsmedchemlett.8b00495

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

Istituto Superiore di Sanita'

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	450-456
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	10
Issue number	4
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00495
Publication status	Published - Apr 11 2019

Access to Document

10.1021/acsmedchemlett.8b00495

Fingerprint Dive into the research topics of 'Novel Cyclic Biphalin Analogues by Ruthenium-Catalyzed Ring Closing Metathesis: in Vivo and in Vitro Biological Profile'. Together they form a unique fingerprint.

Cite this

Stefanucci, A., Lei, W., Pieretti, S., Dimmito, M. P., Luisi, G., Novellino, E., Nowakowski, M., Koźmiński, W., Mirzaie, S., Zengin, G., Streicher, J. M., & Mollica, A. (2019). Novel Cyclic Biphalin Analogues by Ruthenium-Catalyzed Ring Closing Metathesis: in Vivo and in Vitro Biological Profile. ACS Medicinal Chemistry Letters, 10(4), 450-456. https://doi.org/10.1021/acsmedchemlett.8b00495

Novel Cyclic Biphalin Analogues by Ruthenium-Catalyzed Ring Closing Metathesis : in Vivo and in Vitro Biological Profile. / Stefanucci, Azzurra; Lei, Wei; Pieretti, Stefano; Dimmito, Marilisa Pia; Luisi, Grazia; Novellino, Ettore; Nowakowski, Michał; Koźmiński, Wiktor; Mirzaie, Sako; Zengin, Gokhan; Streicher, John M; Mollica, Adriano.

In: ACS Medicinal Chemistry Letters, Vol. 10, No. 4, 11.04.2019, p. 450-456.

Research output: Contribution to journal › Article › peer-review

Stefanucci, A, Lei, W, Pieretti, S, Dimmito, MP, Luisi, G, Novellino, E, Nowakowski, M, Koźmiński, W, Mirzaie, S, Zengin, G, Streicher, JM & Mollica, A 2019, 'Novel Cyclic Biphalin Analogues by Ruthenium-Catalyzed Ring Closing Metathesis: in Vivo and in Vitro Biological Profile', ACS Medicinal Chemistry Letters, vol. 10, no. 4, pp. 450-456. https://doi.org/10.1021/acsmedchemlett.8b00495

Stefanucci, Azzurra ; Lei, Wei ; Pieretti, Stefano ; Dimmito, Marilisa Pia ; Luisi, Grazia ; Novellino, Ettore ; Nowakowski, Michał ; Koźmiński, Wiktor ; Mirzaie, Sako ; Zengin, Gokhan ; Streicher, John M ; Mollica, Adriano. / Novel Cyclic Biphalin Analogues by Ruthenium-Catalyzed Ring Closing Metathesis : in Vivo and in Vitro Biological Profile. In: ACS Medicinal Chemistry Letters. 2019 ; Vol. 10, No. 4. pp. 450-456.

@article{bd3814c5951249a3a63bccc6e1eb5426,

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

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.",

author = "Azzurra Stefanucci and Wei Lei and Stefano Pieretti and Dimmito, {Marilisa Pia} and Grazia Luisi and Ettore Novellino and Micha{\l} Nowakowski and Wiktor Ko{\'z}mi{\'n}ski and Sako Mirzaie and Gokhan Zengin and Streicher, {John M} and Adriano Mollica",

year = "2019",

month = apr,

day = "11",

doi = "10.1021/acsmedchemlett.8b00495",

language = "English",

volume = "10",

pages = "450--456",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

number = "4",

}

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 -