ADME behaviour of some Dmt-DALDA-peptides

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Presentation transcript:

ADME behaviour of some Dmt-DALDA-peptides DruQuaR ADME behaviour of some Dmt-DALDA-peptides Sylvia Van Dorpe1, Iris Vandenbroeck1, Evelien Wynendaele1, Mathieu Verbeken1, Alexandre Novoa2, Dirk Tourwe2, Steven Ballet2 and Bart De Spiegeleer1,* *Corresponding author: bart.despiegeleer@ugent.be (O. Ref.: 2011-252e) 1 DruQuaR group, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium. 2 Department of Organic Chemistry, Faculty of Sciences, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium. Background Desirability . DALDA-peptides: act at µ-opioid receptor µ-opioid receptor: main target in pain treatment Pain management: within central nervous system (CNS) Blood-brain barrier (BBB): main barrier of CNS Thus: peptides should cross the BBB !!! Peptide D-value Ranking P42 0.748 1 P41 0.719 2 SB Aba 0.713 3 EM-2 0.589 4 CTOP 0.575 5 EM-1 0.574 6 TAPS 0.572 7 CTAP 0.564 8 Dermorphin 0.559 9 DAMGO 0.535 10 TAPP 0.384 11 P43 0.278 12 How??? Multiple time regression: influx transfer constant ADME: 15 minutes after IV injection Capillary depletion: brain parenchyma-capillary distribution Efflux: intracerebroventricular injection technique Dmt-DALDA analogues were synthesized: differing in 1 amino acid or constraint structure to improve µ-opioid receptor affinity: . (pi = 1) Dmt-D(Arg)-Phe-Lys-NH2 Dmt-D(Arg)-Phe-Nle-NH2 Dmt-D(Cit)-Phe-Lys-NH2 Dmt-D(Arg)-Aba-Gly-NH2 P41 P42 P43 SB-Aba BBB drugability ranking ADME results [M+H]+ [M+2H]2+ P42 QC: confirmed by MS2 . P41 P42 BBB results . Peptide Kin (µl/(g × min))(1) Capillary fraction (%) (2) Parenchyma fraction (%) (2) kout (min-1) (1) P41 0.37 ± 0.08 23.12 ± 10.26 76.88 ± 10.26 0.058 ± 0.11 P42 0.25 ± 0.25 32.97 ± 9.99 67.03 ± 9.99 -0.039 ± 0.11 P43 -0.31 ± 0.45 19.39 ± 15.81 80.61 ± 15.81 0.027 ± 0.022 SB-Aba 0.45 ± 0.20 30.95 ± 19.75 69.05 ± 19.75 0.096 ± 0.046 P43 SB-Aba Exceptional liver uptake by P42 (1) Regression coefficient ± SEM (2) Fraction ± standard deviation Conclusions Highest BBB influx transfer for P41 and P42 The obtained experimental data indicate that: BBB influx requires the guanidine group of D-Arg; 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 peculiar liver uptake of the peptide. BBB drugability reflected in desirability function: P42 > P41 > SB-Aba >>> dermorphin >> P43 Reference 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, 17, 398-404 (2011).