1 research outputs found
Synthesis of Mixed Opioid Affinity Cyclic Endomorphinâ2 Analogues with Fluorinated Phenylalanines
As
part of our continuing studies on the structureâactivity 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-cÂ[d-Lys-Phe-Phe-Asp]ÂNH<sub>2</sub> (where Dmt = 2âČ,6âČ-dimethyltyrosine), incorporating
fluorinated amino acids: 4-fluorophenylalanine (4-F-Phe), 2,4-difluorophenylalanine
(2,4-F-Phe), or 4-trifluoromethylphenylalanine (4-CF<sub>3</sub>-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 <i>in vitro</i> potencies
and efficacies of all novel analogues were assessed in calcium mobilization
assay. The most potent analogues, Dmt-cÂ[d-Lys-Phe-4-F-Phe-Asp]ÂNH<sub>2</sub> and Dmt-cÂ[d-Lys-Phe-2,4-F-Phe-Asp]ÂNH<sub>2</sub>, were tested <i>in vivo</i> 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 bloodâbrain barrier