Synthesis, characterization and evaluation of anti‐hyperalgesia, anticonvulsant and antioxidant activity of novel VV‐hemorphin‐5 analogs

Abstract

Two series of new VV‐hemorphin‐5 analogs with structures Val–Val–Tyr–Xxx–Trp–Thr–Gln–NH2 and Adam–Val–Val–Tyr–Xxx–Trp–Thr–Gln–NH2, where Xxx is Ac5c (1‐aminocyclopentane‐1‐carboxylic acid), Ac6c (1‐aminocyclohexane‐1‐carboxylic acid), Ac7c (1‐aminocycloheptane‐1‐carboxylic acid), and Adam is the low‐molecular‐weight lipophilic adamantyl building block, were synthesized, characterized electrochemically and evaluated for antioxidant, anti‐hyperalgesia, and anticonvulsant activity. The design of the compounds followed the strategy to improve the propensity for aqueous solubility and/or to increase their affinity for the target receptor or enzyme. The partition coefficient value shows that the peptide scaffold goes from hydrophilic to lipophilic with the increasing size of the cycloalkane ring and even more with the introduction of the adamantane. The peptides C5‐V and C7‐V were the only analogs that provoked an immediate antinociceptive effect changing the mechanical pain threshold. The six new peptide analogs produced a significant and long‐lasting carrageenan model of inflammatory pain in rats. While the adamantane hemorphin analog Ad7‐V was the only compound with the potency to suppress psychomotor seizures in the 6‐Hz test, the C6‐V and Ad6‐V exhibited protective activity against the seizure spread in the maximal electroshock seizure test in mice. The active analogs did not show neurotoxicity or sedative effects. Our results revealed a structure‐related specific activity of a newly designed hemorphin analog that could be used as a template for future modification and preparation of compounds with potential analgesic and anticonvulsant activity.

Synthesis, characterization, and biological study of new synthetic opioid hemorphin‐4 peptides containing sterically restricted nonnatural amino acids

“…[28][29][30][31] As reported in our previous research, we synthesized and characterized new analogs of the bioactive hemorphin peptide family. [9,32] Moreover, through different analytical, physiochemical, biological methods and tests, we demonstrated the relationship between peptide's modification (evaluating both the position and nature of the chosen amino acids) and its activity and affinity properties. [9] Based on the information reported above and in our diligence to find a new type of small bioactive peptide compounds, here we synthesized novel hemorphin-4 analogs containing sterically restricted nonnatural amino acids at the N-terminus, evaluated the stability of the molecule at physiological pH by applying electrochemical, spectral, and DFT approaches and tested the resulting compounds for their in vivo anticonvulsant, antinociceptive, and potential neurotoxicity activity.…”