Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 6, Issue 5, Pages 579-583Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.5b00056
Keywords
Opioid receptor affinity; calcium mobilization assay; antinociceptive activity; blood-brain barrier
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Funding
- Polish Ministry of Science and Higher Education [2013/09/N/NZ7/00646]
- Medical University of Lodz [503/1-156-02/503-01]
- POLONIUM European Agreement (French-Polish exchange program) [30827ZB]
- University of Ferrara
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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.
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