Novel Mixed NOP/Opioid Receptor Peptide Agonists

S. Pacifico; V. Albanese; D. Illuminati; E. Marzola; M. Fabbri; F. Ferrari; V. A. D. Holanda; C. Sturaro; D. Malfacini; C. Ruzza; C. Trapella; D. Preti; Cascio E. Lo; Alessandro Arcovito; Longa S. Della; M. Marangoni; D. Fattori; R. Nassini; G. Calo; R. Guerrini

doi:10.1021/acs.jmedchem.0c02062

Novel Mixed NOP/Opioid Receptor Peptide Agonists

S. Pacifico, V. Albanese, D. Illuminati, E. Marzola, M. Fabbri, F. Ferrari, V. A. D. Holanda, C. Sturaro, D. Malfacini, C. Ruzza^*, C. Trapella, D. Preti^*, Cascio E. Lo, Alessandro Arcovito, Longa S. Della^*, M. Marangoni, D. Fattori, R. Nassini, G. Calo, R. Guerrini

^*Autore corrispondente per questo lavoro

Risultato della ricerca: Contributo in rivista › Articolo

Abstract

The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt1,Xaa5]N/OFQ(1-13)-NH2 were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. The best results in terms of NOP versus mu opioid receptor potency were obtained by substituting both Tyr1 and Thr5 at the N-terminal portion of N/OFQ(1-13)-NH2 with the noncanonical amino acid Dmt. [Dmt1,5]N/OFQ(1-13)-NH2 has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by in silico studies to shed light on the molecular mechanisms by which the peptide binds the active form of the mu receptor. Finally, the compound exerted antitussive effects in an in vivo model of cough.

Lingua originale	Inglese
pagine (da-a)	6656-6669
Numero di pagine	14
Rivista	Journal of Medicinal Chemistry
Volume	64
Numero di pubblicazione	10
DOI	https://doi.org/10.1021/acs.jmedchem.0c02062
Stato di pubblicazione	Pubblicato - 2021

All Science Journal Classification (ASJC) codes

Medicina Molecolare
Nuovi Farmaci

Keywords

MOP
NOP
Nociceptin
Opiod receptors

Accesso al documento

10.1021/acs.jmedchem.0c02062

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Pacifico, S., Albanese, V., Illuminati, D., Marzola, E., Fabbri, M., Ferrari, F., Holanda, V. A. D., Sturaro, C., Malfacini, D., Ruzza, C., Trapella, C., Preti, D., Lo, C. E., Arcovito, A., Della, L. S., Marangoni, M., Fattori, D., Nassini, R., Calo, G., & Guerrini, R. (2021). Novel Mixed NOP/Opioid Receptor Peptide Agonists. Journal of Medicinal Chemistry, 64(10), 6656-6669. https://doi.org/10.1021/acs.jmedchem.0c02062

@article{21bb8b6f43964b05b2661c018c056a8a,

title = "Novel Mixed NOP/Opioid Receptor Peptide Agonists",

abstract = "The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt1,Xaa5]N/OFQ(1-13)-NH2 were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. The best results in terms of NOP versus mu opioid receptor potency were obtained by substituting both Tyr1 and Thr5 at the N-terminal portion of N/OFQ(1-13)-NH2 with the noncanonical amino acid Dmt. [Dmt1,5]N/OFQ(1-13)-NH2 has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by in silico studies to shed light on the molecular mechanisms by which the peptide binds the active form of the mu receptor. Finally, the compound exerted antitussive effects in an in vivo model of cough.",

keywords = "MOP, NOP, Nociceptin, Opiod receptors, MOP, NOP, Nociceptin, Opiod receptors",

author = "S. Pacifico and V. Albanese and D. Illuminati and E. Marzola and M. Fabbri and F. Ferrari and Holanda, \{V. A. D.\} and C. Sturaro and D. Malfacini and C. Ruzza and C. Trapella and D. Preti and Lo, \{Cascio E.\} and Alessandro Arcovito and Della, \{Longa S.\} and M. Marangoni and D. Fattori and R. Nassini and G. Calo and R. Guerrini",

year = "2021",

doi = "10.1021/acs.jmedchem.0c02062",

language = "English",

volume = "64",

pages = "6656--6669",

journal = "Journal of Medicinal Chemistry",

issn = "1520-4804",

publisher = "American Chemical Society",

number = "10",

}

Pacifico, S, Albanese, V, Illuminati, D, Marzola, E, Fabbri, M, Ferrari, F, Holanda, VAD, Sturaro, C, Malfacini, D, Ruzza, C, Trapella, C, Preti, D, Lo, CE, Arcovito, A, Della, LS, Marangoni, M, Fattori, D, Nassini, R, Calo, G & Guerrini, R 2021, 'Novel Mixed NOP/Opioid Receptor Peptide Agonists', Journal of Medicinal Chemistry, vol. 64, n. 10, pagg. 6656-6669. https://doi.org/10.1021/acs.jmedchem.0c02062

TY - JOUR

T1 - Novel Mixed NOP/Opioid Receptor Peptide Agonists

AU - Pacifico, S.

AU - Albanese, V.

AU - Illuminati, D.

AU - Marzola, E.

AU - Fabbri, M.

AU - Ferrari, F.

AU - Holanda, V. A. D.

AU - Sturaro, C.

AU - Malfacini, D.

AU - Ruzza, C.

AU - Trapella, C.

AU - Preti, D.

AU - Lo, Cascio E.

AU - Arcovito, Alessandro

AU - Della, Longa S.

AU - Marangoni, M.

AU - Fattori, D.

AU - Nassini, R.

AU - Calo, G.

AU - Guerrini, R.

PY - 2021

Y1 - 2021

N2 - The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt1,Xaa5]N/OFQ(1-13)-NH2 were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. The best results in terms of NOP versus mu opioid receptor potency were obtained by substituting both Tyr1 and Thr5 at the N-terminal portion of N/OFQ(1-13)-NH2 with the noncanonical amino acid Dmt. [Dmt1,5]N/OFQ(1-13)-NH2 has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by in silico studies to shed light on the molecular mechanisms by which the peptide binds the active form of the mu receptor. Finally, the compound exerted antitussive effects in an in vivo model of cough.

AB - The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt1,Xaa5]N/OFQ(1-13)-NH2 were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. The best results in terms of NOP versus mu opioid receptor potency were obtained by substituting both Tyr1 and Thr5 at the N-terminal portion of N/OFQ(1-13)-NH2 with the noncanonical amino acid Dmt. [Dmt1,5]N/OFQ(1-13)-NH2 has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by in silico studies to shed light on the molecular mechanisms by which the peptide binds the active form of the mu receptor. Finally, the compound exerted antitussive effects in an in vivo model of cough.

KW - MOP

KW - NOP

KW - Nociceptin

KW - Opiod receptors

KW - MOP

KW - NOP

KW - Nociceptin

KW - Opiod receptors

UR - https://publicatt.unicatt.it/handle/10807/181205

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UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85107085688&origin=inward

U2 - 10.1021/acs.jmedchem.0c02062

DO - 10.1021/acs.jmedchem.0c02062

M3 - Article

SN - 1520-4804

VL - 64

SP - 6656

EP - 6669

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 10

ER -

Novel Mixed NOP/Opioid Receptor Peptide Agonists

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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