Discovery of κ Opioid Receptor (KOR)-Selective d-Tetrapeptides with Improved In Vivo Antinociceptive Effect after Peripheral Administration

Azzurra Stefanucci; Alice Della Valle; Giuseppe Scioli; Lorenza Marinaccio; Stefano Pieretti; Paola Minosi; Edina Szucs; Sandor Benyhe; Domiziana Masci; Parthasaradhireddy Tanguturi; Kerry Chou; Deborah Barlow; Karen Houseknecht; John M. Streicher; Adriano Mollica

doi:10.1021/acsmedchemlett.2c00237

Discovery of κ Opioid Receptor (KOR)-Selective d-Tetrapeptides with Improved In Vivo Antinociceptive Effect after Peripheral Administration

Azzurra Stefanucci^*, Alice Della Valle, Giuseppe Scioli, Lorenza Marinaccio, Stefano Pieretti, Paola Minosi, Edina Szucs, Sandor Benyhe, Domiziana Masci, Parthasaradhireddy Tanguturi, Kerry Chou, Deborah Barlow, Karen Houseknecht, John M. Streicher, Adriano Mollica

^*Autore corrispondente per questo lavoro

Risultato della ricerca: Contributo in rivista › Articolo in rivista

Abstract

Peripherally active tetrapeptides as selective kappa opioid receptor (KOR) agonists have been prepared in good overall yields and high purity following solid-phase peptide synthesis via Fmoc protection strategy. Structural modifications at the first and second position of the lead compound FF(D-Nle)R-NH2 (FE200041) were contemplated with aromatic side chains containing D-amino acids, such as (D)-pF-Phe, (D)-mF-Phe, (D)-oF-Phe, which led to highly selective and efficacious KOR agonists endowed with strong antinociceptive activity in vivo following intravenous (i.v.) and subcutaneous (s.c.) administration in the tail flick and formalin tests. These results suggest potential clinical applications in the treatment of neuropathic and inflammatory pain.

Lingua originale	English
pagine (da-a)	1707-1714
Numero di pagine	8
Rivista	ACS Medicinal Chemistry Letters
Volume	13
DOI	https://doi.org/10.1021/acsmedchemlett.2c00237
Stato di pubblicazione	Pubblicato - 2022

Keywords

G protein stimulation
Nociception
Peptides
Selectivity
Tail flick
kappa opioid receptors

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10.1021/acsmedchemlett.2c00237

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Stefanucci, A., Della Valle, A., Scioli, G., Marinaccio, L., Pieretti, S., Minosi, P., Szucs, E., Benyhe, S., Masci, D., Tanguturi, P., Chou, K., Barlow, D., Houseknecht, K., Streicher, J. M., & Mollica, A. (2022). Discovery of κ Opioid Receptor (KOR)-Selective d-Tetrapeptides with Improved In Vivo Antinociceptive Effect after Peripheral Administration. ACS Medicinal Chemistry Letters, 13, 1707-1714. https://doi.org/10.1021/acsmedchemlett.2c00237

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title = "Discovery of κ Opioid Receptor (KOR)-Selective d-Tetrapeptides with Improved In Vivo Antinociceptive Effect after Peripheral Administration",

abstract = "Peripherally active tetrapeptides as selective kappa opioid receptor (KOR) agonists have been prepared in good overall yields and high purity following solid-phase peptide synthesis via Fmoc protection strategy. Structural modifications at the first and second position of the lead compound FF(D-Nle)R-NH2 (FE200041) were contemplated with aromatic side chains containing D-amino acids, such as (D)-pF-Phe, (D)-mF-Phe, (D)-oF-Phe, which led to highly selective and efficacious KOR agonists endowed with strong antinociceptive activity in vivo following intravenous (i.v.) and subcutaneous (s.c.) administration in the tail flick and formalin tests. These results suggest potential clinical applications in the treatment of neuropathic and inflammatory pain.",

keywords = "G protein stimulation, Nociception, Peptides, Selectivity, Tail flick, kappa opioid receptors, G protein stimulation, Nociception, Peptides, Selectivity, Tail flick, kappa opioid receptors",

author = "Azzurra Stefanucci and {Della Valle}, Alice and Giuseppe Scioli and Lorenza Marinaccio and Stefano Pieretti and Paola Minosi and Edina Szucs and Sandor Benyhe and Domiziana Masci and Parthasaradhireddy Tanguturi and Kerry Chou and Deborah Barlow and Karen Houseknecht and Streicher, {John M.} and Adriano Mollica",

year = "2022",

doi = "10.1021/acsmedchemlett.2c00237",

language = "English",

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Stefanucci, A, Della Valle, A, Scioli, G, Marinaccio, L, Pieretti, S, Minosi, P, Szucs, E, Benyhe, S, Masci, D, Tanguturi, P, Chou, K, Barlow, D, Houseknecht, K, Streicher, JM & Mollica, A 2022, 'Discovery of κ Opioid Receptor (KOR)-Selective d-Tetrapeptides with Improved In Vivo Antinociceptive Effect after Peripheral Administration', ACS Medicinal Chemistry Letters, vol. 13, pagg. 1707-1714. https://doi.org/10.1021/acsmedchemlett.2c00237

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T1 - Discovery of κ Opioid Receptor (KOR)-Selective d-Tetrapeptides with Improved In Vivo Antinociceptive Effect after Peripheral Administration

AU - Stefanucci, Azzurra

AU - Della Valle, Alice

AU - Scioli, Giuseppe

AU - Marinaccio, Lorenza

AU - Pieretti, Stefano

AU - Minosi, Paola

AU - Szucs, Edina

AU - Benyhe, Sandor

AU - Masci, Domiziana

AU - Tanguturi, Parthasaradhireddy

AU - Chou, Kerry

AU - Barlow, Deborah

AU - Houseknecht, Karen

AU - Streicher, John M.

AU - Mollica, Adriano

PY - 2022

Y1 - 2022

N2 - Peripherally active tetrapeptides as selective kappa opioid receptor (KOR) agonists have been prepared in good overall yields and high purity following solid-phase peptide synthesis via Fmoc protection strategy. Structural modifications at the first and second position of the lead compound FF(D-Nle)R-NH2 (FE200041) were contemplated with aromatic side chains containing D-amino acids, such as (D)-pF-Phe, (D)-mF-Phe, (D)-oF-Phe, which led to highly selective and efficacious KOR agonists endowed with strong antinociceptive activity in vivo following intravenous (i.v.) and subcutaneous (s.c.) administration in the tail flick and formalin tests. These results suggest potential clinical applications in the treatment of neuropathic and inflammatory pain.

AB - Peripherally active tetrapeptides as selective kappa opioid receptor (KOR) agonists have been prepared in good overall yields and high purity following solid-phase peptide synthesis via Fmoc protection strategy. Structural modifications at the first and second position of the lead compound FF(D-Nle)R-NH2 (FE200041) were contemplated with aromatic side chains containing D-amino acids, such as (D)-pF-Phe, (D)-mF-Phe, (D)-oF-Phe, which led to highly selective and efficacious KOR agonists endowed with strong antinociceptive activity in vivo following intravenous (i.v.) and subcutaneous (s.c.) administration in the tail flick and formalin tests. These results suggest potential clinical applications in the treatment of neuropathic and inflammatory pain.

KW - G protein stimulation

KW - Nociception

KW - Peptides

KW - Selectivity

KW - Tail flick

KW - kappa opioid receptors

KW - G protein stimulation

KW - Nociception

KW - Peptides

KW - Selectivity

KW - Tail flick

KW - kappa opioid receptors

UR - http://hdl.handle.net/10807/267195

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DO - 10.1021/acsmedchemlett.2c00237

M3 - Article

SN - 1948-5875

VL - 13

SP - 1707

EP - 1714

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

ER -

Discovery of κ Opioid Receptor (KOR)-Selective d-Tetrapeptides with Improved In Vivo Antinociceptive Effect after Peripheral Administration

Abstract

Keywords

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