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'

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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

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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.

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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.",

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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

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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.

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DO - 10.1021/acsmedchemlett.8b00495

M3 - Article

C2 - 30996778

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JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 4

ER -

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

Abstract

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