1. 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: (O. Ref.: e)
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
± 0.11
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, (2011).