title: Redoubling the ring size of an endomorphin-2 analog transforms a centrally acting mu-opioid receptor agonist into a pure peripheral analgesic.
abstract: The study reports the synthesis and biological evaluation of two opioid analogs, a monomer and a dimer, obtained as products of the solid-phase, side-chain to side-chain cyclization of the pentapeptide Tyr-d-Lys-Phe-Phe-AspNH2 . The binding affinities to the mu, delta, and kappa opioid receptors, as well as results obtained in a calcium mobilization functional assay are reported. Tyr-[d-Lys-Phe-Phe-Asp]2 -NH2 1 was a potent and selective full agonist of mu with sub-nanomolar affinity, while the dimer (Tyr-[d-Lys-Phe-Phe-Asp]2 -NH2 )2 2 showed a significant mixed mu/kappa affinity, acting as an agonist at the mu. Molecular docking computations were utilized to explain the ability of the dimeric cyclopeptide 2 to interact with the receptor. Interestingly, in spite of the increased ring size, the higher flexibility allowed 2 to fold and fit into the mu receptor binding pocket. Both cyclopeptides were shown to elicit strong antinociceptive activity after intraventricular injection but only cyclomonomer 1 was able to cross the blood-brain barrier. However, the cyclodimer 2 displayed a potent peripheral antinociceptive activity in a mouse model of visceral inflammatory pain. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 309-317, 2016.
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Piekielna
authors.affiliation: Department of Chemistry "G. Ciamician,", University of Bologna, via Selmi 2, Bologna, 40126, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: De Marco
authors.affiliation: Department of Chemistry "G. Ciamician,", University of Bologna, via Selmi 2, Bologna, 40126, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Gentilucci
authors.affiliation: Department of Medical Science, Section of Pharmacology, National Institute of Neuroscience, University of Ferrara, Ferrara, 44121, Italy.
authors.forename: Maria Camilla
authors.initials: MC
authors.lastname: Cerlesi
authors.affiliation: Department of Medical Science, Section of Pharmacology, National Institute of Neuroscience, University of Ferrara, Ferrara, 44121, Italy.
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calo'
authors.affiliation: Institute of Biochemistry, Biological Research Centre of Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Tömböly
authors.affiliation: Di Roberto Artali, Scientia Advice, Desio, MB, 20832, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Artali
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
mesh_terms: D000595:Amino Acid Sequence; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001681:Biological Assay; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003500:Cyclization; D019281:Dimerization; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D017465:Receptors, Opioid, delta / Q000737:chemistry / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000737:chemistry / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D009842:Oligopeptides; D010456:Peptides, Cyclic; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C105294:endomorphin 2; D002118:Calcium
keywords: calcium mobilization; cyclization of peptides; molecular docking; opioid receptors; receptor binding