In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt(1)-DALDA Analogues
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In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt(1)-DALDA Analogues. / Ballet, Steven; Betti, Cecilia; Novoa, Alexandre; Tömböly, Csaba; Nielsen, Carsten Uhd; Helms, Hans Christian; Lesniak, Anna; Kleczkowska, Patrycja; Chung, Nga N; Lipkowski, Andrzej W; Brodin, Birger; Tourwé, Dirk; Schiller, Peter W.
In: ACS Medicinal Chemistry Letters, Vol. 5, No. 4, 10.04.2014, p. 352-357.Research output: Contribution to journal › Journal article › peer-review
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TY - JOUR
T1 - In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt(1)-DALDA Analogues
AU - Ballet, Steven
AU - Betti, Cecilia
AU - Novoa, Alexandre
AU - Tömböly, Csaba
AU - Nielsen, Carsten Uhd
AU - Helms, Hans Christian
AU - Lesniak, Anna
AU - Kleczkowska, Patrycja
AU - Chung, Nga N
AU - Lipkowski, Andrzej W
AU - Brodin, Birger
AU - Tourwé, Dirk
AU - Schiller, Peter W
PY - 2014/4/10
Y1 - 2014/4/10
N2 - In this study the μ opioid receptor (MOR) ligands DALDA (Tyr-d-Arg-Phe-Lys-NH2) and Dmt(1)-DALDA (Dmt-d-Arg-Phe-Lys-NH2, Dmt = 2',6'-dimethyltyrosine) were glycosylated at the N- or C-terminus. Subsequently, the modified peptides were subjected to in vitro and in vivo evaluation. In contrast to the N-terminally modified peptide (3), all peptide analogues derivatized at the C-terminus (4-7) proved to possess high affinity and agonist potency at both MOR and DOR (δ opioid receptor). Results of the Caco-2 monolayer permeation, as well as in vitro blood-brain barrier model experiments, showed that, in the case of compound 4, the glycosylation only slightly diminished the lumen-to-blood and blood-to-lumen transport. Altogether, these experiments were indicative of transcellular transport but not active transport. In vivo assays demonstrated that the peptides were capable of (i) crossing the blood-brain barrier (BBB) and (ii) activating both the spinal ascending as well as the descending opioid pathways, as determined by the tail-flick and hot-plate assays, respectively. In contrast to the highly selective MOR agonist Dmt(1)-DALDA 1, compounds 4-7 are mixed MOR/DOR agonists, expected to produce reduced opioid-related side effects.
AB - In this study the μ opioid receptor (MOR) ligands DALDA (Tyr-d-Arg-Phe-Lys-NH2) and Dmt(1)-DALDA (Dmt-d-Arg-Phe-Lys-NH2, Dmt = 2',6'-dimethyltyrosine) were glycosylated at the N- or C-terminus. Subsequently, the modified peptides were subjected to in vitro and in vivo evaluation. In contrast to the N-terminally modified peptide (3), all peptide analogues derivatized at the C-terminus (4-7) proved to possess high affinity and agonist potency at both MOR and DOR (δ opioid receptor). Results of the Caco-2 monolayer permeation, as well as in vitro blood-brain barrier model experiments, showed that, in the case of compound 4, the glycosylation only slightly diminished the lumen-to-blood and blood-to-lumen transport. Altogether, these experiments were indicative of transcellular transport but not active transport. In vivo assays demonstrated that the peptides were capable of (i) crossing the blood-brain barrier (BBB) and (ii) activating both the spinal ascending as well as the descending opioid pathways, as determined by the tail-flick and hot-plate assays, respectively. In contrast to the highly selective MOR agonist Dmt(1)-DALDA 1, compounds 4-7 are mixed MOR/DOR agonists, expected to produce reduced opioid-related side effects.
U2 - 10.1021/ml4004765
DO - 10.1021/ml4004765
M3 - Journal article
C2 - 24839540
VL - 5
SP - 352
EP - 357
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 4
ER -
ID: 112718768