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

Pharmacology

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

3 Scopus citations

Abstract

Peripherally active tetrapeptides as selective κ 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.

Original language	English (US)
Pages (from-to)	1707-1714
Number of pages	8
Journal	ACS Medicinal Chemistry Letters
Volume	13
Issue number	11
DOIs	https://doi.org/10.1021/acsmedchemlett.2c00237
State	Published - Nov 10 2022

Keywords

G protein stimulation
Nociception
Peptides
Selectivity
Tail flick
κ opioid receptors

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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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(11), 1707-1714. https://doi.org/10.1021/acsmedchemlett.2c00237

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, no. 11, pp. 1707-1714. https://doi.org/10.1021/acsmedchemlett.2c00237

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abstract = "Peripherally active tetrapeptides as selective κ 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.",

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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

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

Abstract

Keywords

ASJC Scopus subject areas

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