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ADME behaviour of some Dmt-DALDA-peptide derivatives

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Abstract
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.
Keywords
desirability, peptide, Blood-brain barrier, ADME

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Chicago
Van Dorpe, Sylvia, Iris Vandenbroeck, Evelien Wynendaele, Mathieu Verbeken, Alexandre Novoa, Dirk Tourwé, Steven Ballet, and Bart De Spiegeleer. 2011. “ADME Behaviour of Some Dmt-DALDA-peptide Derivatives.” In 3rd Scientific Afternoon, Abstracts.
APA
Van Dorpe, S., Vandenbroeck, I., Wynendaele, E., Verbeken, M., Novoa, A., Tourwé, D., Ballet, S., et al. (2011). ADME behaviour of some Dmt-DALDA-peptide derivatives. 3rd scientific afternoon, Abstracts. Presented at the 3rd Scientific Afternoon (FFW - 2011).
Vancouver
1.
Van Dorpe S, Vandenbroeck I, Wynendaele E, Verbeken M, Novoa A, Tourwé D, et al. ADME behaviour of some Dmt-DALDA-peptide derivatives. 3rd scientific afternoon, Abstracts. 2011.
MLA
Van Dorpe, Sylvia, Iris Vandenbroeck, Evelien Wynendaele, et al. “ADME Behaviour of Some Dmt-DALDA-peptide Derivatives.” 3rd Scientific Afternoon, Abstracts. 2011. Print.
@inproceedings{1235371,
  abstract     = {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 {\textmu}-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 {\textmu}-selective dermorphin, is of particular interest since it has been identified as a more potent \ensuremath{\mu}-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 {\textmu}-opioid peptides was evaluated using our desirability criterion. The obtained experimental data indicate that replacing the \ensuremath{\epsilon}-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.},
  author       = {Van Dorpe, Sylvia and Vandenbroeck, Iris and Wynendaele, Evelien and Verbeken, Mathieu and Novoa, Alexandre and Tourw{\'e}, Dirk and Ballet, Steven and De Spiegeleer, Bart},
  booktitle    = {3rd scientific afternoon, Abstracts},
  keyword      = {desirability,peptide,Blood-brain barrier,ADME},
  language     = {eng},
  location     = {Ghent, Belgium},
  title        = {ADME behaviour of some Dmt-DALDA-peptide derivatives},
  year         = {2011},
}