Blood-brain barrier and ADME properties of selected 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 [1]. The present study describes the blood-brain barrier (BBB) transport behaviour of some related Dmt-DALDA analogues as well as their ADME 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 [2]. The obtained experimental data indicate that: i) BBB influx requires the guanidine group of D-Arg, with the presence of the ε-amino group of Lys of lesser importance; ii) BBB efflux is only observed if the guanidine group of D-Arg is oxidised to D-citrulline; iii) a higher BBB drugability of the Dmt-DALDA analogues compared to dermorphin was objectively calculated by the desirability criterion values; iv) replacing the ε-amino group of D-Arg with a methyl group, while retaining the guanidine group, yielded a peculiar liver uptake of the peptide. References: [1] P. Riba, Y. Ben, T.M.D. Nguyen, S. Furst, P.W. Schiller and N.M. Lee. [Dmt(1)]DALDA is highly selective and potent at mu opioid receptors, but is not cross-tolerant with systemic morphine, Current Medicinal Chemistry 9(1) (2002) 31-39. [2] S. Van Dorpe, A. Adriaens, S. Vermeire, I. Polis, K. Peremans and B. De Spiegeleer. Desirability function combining metabolic stability and functionality of peptides, Journal of Peptide Science (2011) doi 10.1002/psc.1323