title: Cyclic side-chain-linked opioid analogs utilizing cis- and  trans-4-aminocyclohexyl-D-alanine.
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.
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Piekielna
authors.affiliation: Department of Chemistry 'G. Ciamician', University of Bologna, via Selmi 2, 40126 Bologna, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Gentilucci
authors.affiliation: Department of Chemistry 'G. Ciamician', University of Bologna, via Selmi 2, 40126 Bologna, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: De Marco
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Perlikowska
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Adamska
authors.affiliation: TriMen Chemicals Ltd, 92-318 Lodz, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Olczak
authors.affiliation: TriMen Chemicals Ltd, 92-318 Lodz, Poland.
authors.forename: Marzena
authors.initials: M
authors.lastname: Mazur
authors.affiliation: Scientia Advice, 20832 Desio (MB), Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Artali
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, 90-924 Lodz, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Modranka
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, 90-924 Lodz, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Janecki
authors.affiliation: Institute of Biochemistry, Biological Research Centre of Hungarian Academy of Sciences, 6701 Szeged, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Tömböly
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland. Electronic address: anna.janecka@umed.lodz.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D003500:Cyclization; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: C521364:4-aminocyclohexylalanine; D003510:Cyclohexanes; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000409:Alanine