Conclusions

Medicinal Chemistry Group: Opioid Bioactivity

Since most opioid peptides must be covalently modified to ensure stability and pass through the BBB, the fact that bis-Dmt-pyrazinone-containing compounds were transmitted without modification is highly significant. In order to cross the BBB opioid peptides usually are chemically modified, such as coupling to D-glucose, or other glycosidic residues, triglycerides, 1-adamantane, halogens, an antibody, biotin, bulky organic molecules, or esterification of the C-terminal carboxylate or O-acylation of the phenolic hydroxyl group of Tyr. And further, it was unnecessary to absorb the opioidmimetic on polysorbate 80. Considering that our opioidmimetic substances contain the unusual amino acid Dmt, unbranched alkyl chains and a pyrazinone ring, they might be relatively more stable under physiological conditions in vivo than natural opioid peptides, which have short half-lives and do not readily pass through membrane barriers.

These studies also permitted transit through the BBB without using MDR-1 knockout mice. However, considering that a differential analgesic sensitivity exists in different mice strains to morphine and opioid peptides, it may be possible these compounds might exhibit strain differences that might affect its activity in vivo.