Synthesis of mixed opioid affinity cyclic endomorphin-2 analogues with fluorinated phenylalanines

Justyna Piekielna, Renata Perlikowska, Jean Claude Do-Rego, Jean Luc Do-Rego, Maria Camilla Cerlesi, Girolamo Calo, Alicja Kluczyk, Krzysztof Łapiński, C. Tömböly, Anna Janecka

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

As part of our continuing studies on the structure-activity relationships of cyclic pentapeptides based on the structure of endomorphin-2 (EM-2), we report here the synthesis and biological activities of a new series of analogues of a general sequence Tyr/Dmt-c[d-Lys-Phe-Phe-Asp]NH2 (where Dmt = 2′,6′-dimethyltyrosine), incorporating fluorinated amino acids: 4-fluorophenylalanine (4-F-Phe), 2,4-difluorophenylalanine (2,4-F-Phe), or 4-trifluoromethylphenylalanine (4-CF3-Phe) instead of the Phe residue in position 3 or 4. Depending on the fluorinated amino acid residue and its position in the sequence, analogues were mixed, high affinity MOP/KOP receptor agonists, MOP/DOP/KOP agonists, or selective KOP agonists. The in vitro potencies and efficacies of all novel analogues were assessed in calcium mobilization assay. The most potent analogues, Dmt-c[d-Lys-Phe-4-F-Phe-Asp]NH2 and Dmt-c[d-Lys-Phe-2,4-F-Phe-Asp]NH2, were tested in vivo in the mouse hot-plate test. They produced strong antinociceptive effect not only after intracerebroventricular but also after intraperitoneal injection, indicating that they were able to cross the blood-brain barrier.

Original languageEnglish
Pages (from-to)579-583
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume6
Issue number5
DOIs
Publication statusPublished - May 14 2015

Fingerprint

p-Fluorophenylalanine
Phenylalanine
lysylphenylalanine
Opioid Analgesics
Amino Acids
Structure-Activity Relationship
Bioactivity
Intraperitoneal Injections
Blood-Brain Barrier
Assays
Calcium
endomorphin 2

Keywords

  • antinociceptive activity
  • blood-brain barrier
  • calcium mobilization assay
  • Opioid receptor affinity

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

Piekielna, J., Perlikowska, R., Do-Rego, J. C., Do-Rego, J. L., Cerlesi, M. C., Calo, G., ... Janecka, A. (2015). Synthesis of mixed opioid affinity cyclic endomorphin-2 analogues with fluorinated phenylalanines. ACS Medicinal Chemistry Letters, 6(5), 579-583. https://doi.org/10.1021/acsmedchemlett.5b00056

Synthesis of mixed opioid affinity cyclic endomorphin-2 analogues with fluorinated phenylalanines. / Piekielna, Justyna; Perlikowska, Renata; Do-Rego, Jean Claude; Do-Rego, Jean Luc; Cerlesi, Maria Camilla; Calo, Girolamo; Kluczyk, Alicja; Łapiński, Krzysztof; Tömböly, C.; Janecka, Anna.

In: ACS Medicinal Chemistry Letters, Vol. 6, No. 5, 14.05.2015, p. 579-583.

Research output: Contribution to journalArticle

Piekielna, J, Perlikowska, R, Do-Rego, JC, Do-Rego, JL, Cerlesi, MC, Calo, G, Kluczyk, A, Łapiński, K, Tömböly, C & Janecka, A 2015, 'Synthesis of mixed opioid affinity cyclic endomorphin-2 analogues with fluorinated phenylalanines', ACS Medicinal Chemistry Letters, vol. 6, no. 5, pp. 579-583. https://doi.org/10.1021/acsmedchemlett.5b00056
Piekielna, Justyna ; Perlikowska, Renata ; Do-Rego, Jean Claude ; Do-Rego, Jean Luc ; Cerlesi, Maria Camilla ; Calo, Girolamo ; Kluczyk, Alicja ; Łapiński, Krzysztof ; Tömböly, C. ; Janecka, Anna. / Synthesis of mixed opioid affinity cyclic endomorphin-2 analogues with fluorinated phenylalanines. In: ACS Medicinal Chemistry Letters. 2015 ; Vol. 6, No. 5. pp. 579-583.
@article{7145e994b9cb42bd9fdd26277ad55bbb,
title = "Synthesis of mixed opioid affinity cyclic endomorphin-2 analogues with fluorinated phenylalanines",
abstract = "As part of our continuing studies on the structure-activity relationships of cyclic pentapeptides based on the structure of endomorphin-2 (EM-2), we report here the synthesis and biological activities of a new series of analogues of a general sequence Tyr/Dmt-c[d-Lys-Phe-Phe-Asp]NH2 (where Dmt = 2′,6′-dimethyltyrosine), incorporating fluorinated amino acids: 4-fluorophenylalanine (4-F-Phe), 2,4-difluorophenylalanine (2,4-F-Phe), or 4-trifluoromethylphenylalanine (4-CF3-Phe) instead of the Phe residue in position 3 or 4. Depending on the fluorinated amino acid residue and its position in the sequence, analogues were mixed, high affinity MOP/KOP receptor agonists, MOP/DOP/KOP agonists, or selective KOP agonists. The in vitro potencies and efficacies of all novel analogues were assessed in calcium mobilization assay. The most potent analogues, Dmt-c[d-Lys-Phe-4-F-Phe-Asp]NH2 and Dmt-c[d-Lys-Phe-2,4-F-Phe-Asp]NH2, were tested in vivo in the mouse hot-plate test. They produced strong antinociceptive effect not only after intracerebroventricular but also after intraperitoneal injection, indicating that they were able to cross the blood-brain barrier.",
keywords = "antinociceptive activity, blood-brain barrier, calcium mobilization assay, Opioid receptor affinity",
author = "Justyna Piekielna and Renata Perlikowska and Do-Rego, {Jean Claude} and Do-Rego, {Jean Luc} and Cerlesi, {Maria Camilla} and Girolamo Calo and Alicja Kluczyk and Krzysztof Łapiński and C. T{\"o}mb{\"o}ly and Anna Janecka",
year = "2015",
month = "5",
day = "14",
doi = "10.1021/acsmedchemlett.5b00056",
language = "English",
volume = "6",
pages = "579--583",
journal = "ACS Medicinal Chemistry Letters",
issn = "1948-5875",
publisher = "American Chemical Society",
number = "5",

}

TY - JOUR

T1 - Synthesis of mixed opioid affinity cyclic endomorphin-2 analogues with fluorinated phenylalanines

AU - Piekielna, Justyna

AU - Perlikowska, Renata

AU - Do-Rego, Jean Claude

AU - Do-Rego, Jean Luc

AU - Cerlesi, Maria Camilla

AU - Calo, Girolamo

AU - Kluczyk, Alicja

AU - Łapiński, Krzysztof

AU - Tömböly, C.

AU - Janecka, Anna

PY - 2015/5/14

Y1 - 2015/5/14

N2 - As part of our continuing studies on the structure-activity relationships of cyclic pentapeptides based on the structure of endomorphin-2 (EM-2), we report here the synthesis and biological activities of a new series of analogues of a general sequence Tyr/Dmt-c[d-Lys-Phe-Phe-Asp]NH2 (where Dmt = 2′,6′-dimethyltyrosine), incorporating fluorinated amino acids: 4-fluorophenylalanine (4-F-Phe), 2,4-difluorophenylalanine (2,4-F-Phe), or 4-trifluoromethylphenylalanine (4-CF3-Phe) instead of the Phe residue in position 3 or 4. Depending on the fluorinated amino acid residue and its position in the sequence, analogues were mixed, high affinity MOP/KOP receptor agonists, MOP/DOP/KOP agonists, or selective KOP agonists. The in vitro potencies and efficacies of all novel analogues were assessed in calcium mobilization assay. The most potent analogues, Dmt-c[d-Lys-Phe-4-F-Phe-Asp]NH2 and Dmt-c[d-Lys-Phe-2,4-F-Phe-Asp]NH2, were tested in vivo in the mouse hot-plate test. They produced strong antinociceptive effect not only after intracerebroventricular but also after intraperitoneal injection, indicating that they were able to cross the blood-brain barrier.

AB - As part of our continuing studies on the structure-activity relationships of cyclic pentapeptides based on the structure of endomorphin-2 (EM-2), we report here the synthesis and biological activities of a new series of analogues of a general sequence Tyr/Dmt-c[d-Lys-Phe-Phe-Asp]NH2 (where Dmt = 2′,6′-dimethyltyrosine), incorporating fluorinated amino acids: 4-fluorophenylalanine (4-F-Phe), 2,4-difluorophenylalanine (2,4-F-Phe), or 4-trifluoromethylphenylalanine (4-CF3-Phe) instead of the Phe residue in position 3 or 4. Depending on the fluorinated amino acid residue and its position in the sequence, analogues were mixed, high affinity MOP/KOP receptor agonists, MOP/DOP/KOP agonists, or selective KOP agonists. The in vitro potencies and efficacies of all novel analogues were assessed in calcium mobilization assay. The most potent analogues, Dmt-c[d-Lys-Phe-4-F-Phe-Asp]NH2 and Dmt-c[d-Lys-Phe-2,4-F-Phe-Asp]NH2, were tested in vivo in the mouse hot-plate test. They produced strong antinociceptive effect not only after intracerebroventricular but also after intraperitoneal injection, indicating that they were able to cross the blood-brain barrier.

KW - antinociceptive activity

KW - blood-brain barrier

KW - calcium mobilization assay

KW - Opioid receptor affinity

UR - http://www.scopus.com/inward/record.url?scp=84929314479&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929314479&partnerID=8YFLogxK

U2 - 10.1021/acsmedchemlett.5b00056

DO - 10.1021/acsmedchemlett.5b00056

M3 - Article

AN - SCOPUS:84929314479

VL - 6

SP - 579

EP - 583

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 5

ER -