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.
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz , 92-215 Lodz, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Piekielna
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz , 92-215 Lodz, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Perlikowska
authors.affiliation: Institut de Recherche et d'Innovation Biomédicale (IRIB), Service Commun d'Analyse Comportementale (SCAC), Faculté de Médecine et Pharmacie, Université de Rouen , 76183 Rouen Cedex, France ; Centre National de la Recherche Scientifique (CNRS) , 75794 Paris Cedex, France.
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: do-Rego
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Regional Platform for Cell Imaging (PRIMACEN), Faculté des Sciences et Techniques, Université de Rouen , 76821 Mont-Saint-Aignan Cedex, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: do-Rego
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and Italian Institute of Neuroscience, University of Ferrara , 44121 Ferrara, Italy.
authors.forename: Maria Camilla
authors.initials: MC
authors.lastname: Cerlesi
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and Italian Institute of Neuroscience, University of Ferrara , 44121 Ferrara, Italy.
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calo
authors.affiliation: Faculty of Chemistry, University of Wroclaw , 50-383 Wroclaw, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Kluczyk
authors.affiliation: TriMen Chemicals Ltd. , 92-318 Lodz, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Łapiński
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 , 92-215 Lodz, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
keywords: Opioid receptor affinity; antinociceptive activity; blood−brain barrier; calcium mobilization assay