Cyclic side-chain-linked opioid analogs utilizing cis- and trans-4-aminocyclohexyl-d-alanine

Justyna Piekielna, Luca Gentilucci, Rossella De Marco, Renata Perlikowska, Anna Adamska, Jacek Olczak, Marzena Mazur, Roberto Artali, Jakub Modranka, Tomasz Janecki, C. Tömböly, Anna Janecka

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Cyclization of linear sequences is a well recognized tool in opioid peptide chemistry for generating analogs with improved bioactivities. Cyclization can be achieved through various bridging bonds between peptide ends or side-chains. In our earlier paper we have reported the synthesis and biological activity of a cyclic peptide, Tyr-c[d-Lys-Phe-Phe-Asp]NH2 (1), which can be viewed as an analog of endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2). Cyclization was achieved through an amide bond between side-chains of d-Lys and Asp residues. Here, to increase rigidity of the cyclic structure, we replaced d-Lys with cis- or trans-4-aminocyclohexyl-d-alanine (d-ACAla). Two sets of analogs incorporating either Tyr or Dmt (2′,6′-dimethyltyrosine) residues in position 1 were synthesized. In the binding studies the analog incorporating Dmt and trans-d-ACAla showed high affinity for both, μ- and δ-opioid receptors (MOR and DOR, respectively) and moderate affinity for the κ-opioid receptor (KOR), while analog with Dmt and cis-d-ACAla was exceptionally MOR-selective. Conformational analyses by NMR and molecular docking studies have been performed to investigate the molecular structural features responsible for the noteworthy MOR selectivity.

Original languageEnglish
Pages (from-to)6545-6551
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number23
DOIs
Publication statusPublished - Dec 1 2014

Fingerprint

Cyclization
Alanine
Opioid Analgesics
Opioid Receptors
Bioactivity
Molecular Docking Simulation
Cyclic Peptides
Opioid Peptides
Viperidae
Amides
Rigidity
Nuclear magnetic resonance
Peptides
endomorphin 2

Keywords

  • Conformational analysis
  • Cyclic analogs
  • Molecular docking
  • Opioid peptides
  • Opioid receptor binding
  • Unnatural amino acids

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Medicine(all)

Cite this

Piekielna, J., Gentilucci, L., De Marco, R., Perlikowska, R., Adamska, A., Olczak, J., ... Janecka, A. (2014). Cyclic side-chain-linked opioid analogs utilizing cis- and trans-4-aminocyclohexyl-d-alanine. Bioorganic and Medicinal Chemistry, 22(23), 6545-6551. https://doi.org/10.1016/j.bmc.2014.10.022

Cyclic side-chain-linked opioid analogs utilizing cis- and trans-4-aminocyclohexyl-d-alanine. / Piekielna, Justyna; Gentilucci, Luca; De Marco, Rossella; Perlikowska, Renata; Adamska, Anna; Olczak, Jacek; Mazur, Marzena; Artali, Roberto; Modranka, Jakub; Janecki, Tomasz; Tömböly, C.; Janecka, Anna.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 23, 01.12.2014, p. 6545-6551.

Research output: Contribution to journalArticle

Piekielna, J, Gentilucci, L, De Marco, R, Perlikowska, R, Adamska, A, Olczak, J, Mazur, M, Artali, R, Modranka, J, Janecki, T, Tömböly, C & Janecka, A 2014, 'Cyclic side-chain-linked opioid analogs utilizing cis- and trans-4-aminocyclohexyl-d-alanine', Bioorganic and Medicinal Chemistry, vol. 22, no. 23, pp. 6545-6551. https://doi.org/10.1016/j.bmc.2014.10.022
Piekielna J, Gentilucci L, De Marco R, Perlikowska R, Adamska A, Olczak J et al. Cyclic side-chain-linked opioid analogs utilizing cis- and trans-4-aminocyclohexyl-d-alanine. Bioorganic and Medicinal Chemistry. 2014 Dec 1;22(23):6545-6551. https://doi.org/10.1016/j.bmc.2014.10.022
Piekielna, Justyna ; Gentilucci, Luca ; De Marco, Rossella ; Perlikowska, Renata ; Adamska, Anna ; Olczak, Jacek ; Mazur, Marzena ; Artali, Roberto ; Modranka, Jakub ; Janecki, Tomasz ; Tömböly, C. ; Janecka, Anna. / Cyclic side-chain-linked opioid analogs utilizing cis- and trans-4-aminocyclohexyl-d-alanine. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 22, No. 23. pp. 6545-6551.
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