Synthesis and analgesic activity of new analogs of FELL tetrapeptide containing D-Phe in the first position

Abstract

Pain, whether acute or chronic, is one of the most unpleasant experiences. It can have different origins and long-term effects on the body starting from the trivial once such as physical discomfort, accompanying by emotional distress and going to the more serious like depression, anxiety, and social isolation. The removal and proper treatment of the pain is a problem highly dependent on both the source and the individual features of each organism. Herein the view is turned on investigation of activity of new analogs of natural FELL peptide as a promising alternative of the existing antipain molecules. All targeted compounds are obtained by means of conventional peptide synthesis on solid support using standard Fmoc/OtBu approach and their analgesic activity was evaluated by Paw-pressure (Randall-Selitto) test. Determination of the in vivo analgesic activity of the newly synthesized substances showed that the substitution of both Leu (BB11) with Val residues (BB8) increased PPT of the experimental animals on the 10th min, compared to the values after the nonmodified parent molecule injection. On the 20th and the 30th min, BB8 analgesic activity was comparable to BB11 and further a decrease in the PPT was observed. In addition, compared to the controls, analgesia exists until the end of the monitored period of 50 min. The other three newly synthesized substances including Nle (BB6), Ile (BB7) and triple Leu (BB5) instead of double Leu residues showed time-varying short-term analgesic activity, which did not reach that of the parent molecule BB11. Final results show that D-Phe in a first position of the molecule, combined with both Leu residues in the third and fourth positions are the best combination concerning analgesic activity. In addition, lengthening the peptide chain by adding one more hydrophobic residue has also a positive effect on the obtained analgesia. Cytotoxicity of final molecules is significantly lower than those of the positive control SLS, combined with complete hydrolytic stability, which allows their safety use in pharmacy.

Keywords

• FELL analogs
• Analgesic activity
• Unnatural amino acids
• D-amino acids
• Cytotoxicity