title: Ring size in cyclic endomorphin-2 analogs modulates receptor binding affinity and selectivity.
abstract: The study reports the solid-phase synthesis and biological evaluation of a series of new side chain-to-side chain cyclized opioid peptide analogs of the general structure Tyr-[D-Xaa-Phe-Phe-Asp]NH2, where Xaa = Lys (1), Orn (2), Dab (3), or Dap (4) (Dab = 2,4-diaminobutyric acid, Dap = 2,3-diaminopropionic acid), containing 17- to 14-membered rings. The influence of the ring size on binding to the MOP, DOP and KOP opioid receptors was studied. In general, the reduction of the size of the macrocyclic ring increased the selectivity for the MOP receptor. The cyclopeptide incorporating Xaa = Lys displayed subnanomolar MOP affinity but modest selectivity over the KOP receptor, while the analog with the Orn residue showed increased affinity and selectivity for MOP. The analog with Dab was a weak MOP agonist and did not bind to the other two opioid receptors. Finally, the peptide with Xaa = Dap was completely MOP receptor-selective with subnanomolar affinity. Interestingly, the deletion of one Phe residue from 1 led to the 14-membered Tyr-c[D-Lys-Phe-Asp]NH2 (5), a potent and selective MOP receptor ligand. The in vitro potencies of the new analogs were determined in a calcium mobilization assay performed in Chinese Hamster Ovary (CHO) cells expressing human recombinant opioid receptors and chimeric G proteins. A good correlation between binding and the functional test results was observed. The influence of the ring size, solid support and the N-terminal protecting group on the formation of cyclodimers was studied.
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland. anna.janecka@umed.lodz.pl.
authors.forename: Justyna
authors.initials: J
authors.lastname: Piekielna
authors.forename: Alicja
authors.initials: A
authors.lastname: Kluczyk
authors.forename: Luca
authors.initials: L
authors.lastname: Gentilucci
authors.forename: Maria Camilla
authors.initials: MC
authors.lastname: Cerlesi
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calo'
authors.forename: Csaba
authors.initials: C
authors.lastname: Tomböly
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Łapiński
authors.forename: Tomasz
authors.initials: T
authors.lastname: Janecki
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
mesh_terms: D000595:Amino Acid Sequence; D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011957:Receptors, Opioid; C105294:endomorphin 2