ADME behaviour of some Dmt-DALDA-peptide derivatives

Most naturally occurring opioid peptides, such as the endomorphins, are not highly selective for a single opioid receptor type. However, it was observed that dermorphins show a very high µ-opioid receptor selectivity compared to most other natural peptides. The 3+ charged tetrapeptide Dmt-DALDA (Dmt-D(Arg)-Phe-Lys-NH2), an analogue of the µ-selective dermorphin, is of particular interest since it has been identified as a more potent μ-opioid receptor agonist compared to dermorphin. The present study describes the ADME behaviour of four related Dmt-DALDA analogues including their blood-brain barrier (BBB) transport properties. The influx transfer constant from serum into mouse brain was determined by multiple time regression while the efflux kinetics were investigated with the intracerebroventricular injection technique. Brain parenchyma-capillary cell distribution was evaluated by capillary depletion. In addition, the functional drugability of these µ-opioid peptides was evaluated using our desirability criterion. The obtained experimental data indicate that replacing the ε-amino group of Lys with a methyl group, while retaining the guanidine group and the other amino acids like Dmt-DALDA, yielded a significantly higher liver uptake of the peptide. Moreover, BBB influx transfer was structurally related to the presence of the guanidine group of D-Arg