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Variation of the net charge, lipophilicity, and side chain flexibility in Dmt¹-DALDA: effect on opioid activity and biodistribution

Alexandre Novoa, Sylvia Van Dorpe, Evelien Wynendaele UGent, Mariana Spetea, Nathalie Bracke, Sofie Stalmans, Cecilia Betti, Nga N Chung, Carole Lemieux, Johannes Zuegg, et al. (2012) JOURNAL OF MEDICINAL CHEMISTRY. 55(22). p.9549-9561
abstract
The influence of the side chain charges of the second and fourth amino acid residues in the peptidic mu opioid lead agonist Dmt-D-Arg-Phe-Lys-NH2. ([Dmt(1)-DALDA) was examined. Additionally, to increase the overall lipophilicity of [Dmt(1)]-DALDA and to investigate the Phe(3) side chain flexibility, the final amide bond was N-methylated and Phe(3) was replaced by a constrained aminobenzazepine analogue. The in vitro receptor binding and activity of the peptides, as well as their in vivo transport (brain in- and efflux and tissue biodistribution) and antinociceptive properties after peripheral administration (ip and sc) in mice were determined. The structural modifications result in significant shifts of receptor binding, activity, and transport, properties. Strikingly, while [Dmt(1)]-DALDA and its N-methyl analogue, Dmt-D-Arg-Phe-NMeLys-NH2, showed a long-lasting antinociceptive effect (>7 h), the peptides with D-Cit(2) generate potent antinociception more rapidly (maximal effect at 1h postinjection) but also lose their analgesic activity faster when compared to [Dmt(1)]-DALDA. and [Dmit(1),NMeLys(4)]-DALDA.
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alternative title
Variation of the net charge, lipophilicity, and side chain flexibility in Dmt1-DALDA : effect on opioid activity and biodistribution
Variation of the net charge, lipophilicity, and side chain flexibility in Dmt(1)-DALDA : effect on opioid activity and biodistribution
year
type
journalArticle (original)
publication status
published
subject
keyword
TETRAPEPTIDE ANALOGS, METABOLIC STABILITY, PHARMACOLOGICAL CHARACTERIZATION, IN-VITRO, CYCLIC ENKEPHALIN ANALOGS, 1 RECEPTOR ANTAGONIST, OPIATE RECEPTOR, AMINO-ACID, PEPTIDE, BRAIN
journal title
JOURNAL OF MEDICINAL CHEMISTRY
J. Med. Chem.
volume
55
issue
22
pages
9549 - 9561
Web of Science type
Article
Web of Science id
000311461500013
JCR category
CHEMISTRY, MEDICINAL
JCR impact factor
5.614 (2012)
JCR rank
3/59 (2012)
JCR quartile
1 (2012)
ISSN
0022-2623
DOI
10.1021/jm3008079
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2151465
handle
http://hdl.handle.net/1854/LU-2151465
date created
2012-06-13 15:02:44
date last changed
2016-12-19 15:42:06
@article{2151465,
  abstract     = {The influence of the side chain charges of the second and fourth amino acid residues in the peptidic mu opioid lead agonist Dmt-D-Arg-Phe-Lys-NH2. ([Dmt(1)-DALDA) was examined. Additionally, to increase the overall lipophilicity of [Dmt(1)]-DALDA and to investigate the Phe(3) side chain flexibility, the final amide bond was N-methylated and Phe(3) was replaced by a constrained aminobenzazepine analogue. The in vitro receptor binding and activity of the peptides, as well as their in vivo transport (brain in- and efflux and tissue biodistribution) and antinociceptive properties after peripheral administration (ip and sc) in mice were determined. The structural modifications result in significant shifts of receptor binding, activity, and transport, properties. Strikingly, while [Dmt(1)]-DALDA and its N-methyl analogue, Dmt-D-Arg-Phe-NMeLys-NH2, showed a long-lasting antinociceptive effect ({\textrangle}7 h), the peptides with D-Cit(2) generate potent antinociception more rapidly (maximal effect at 1h postinjection) but also lose their analgesic activity faster when compared to [Dmt(1)]-DALDA. and [Dmit(1),NMeLys(4)]-DALDA.},
  author       = {Novoa, Alexandre and Van Dorpe, Sylvia and Wynendaele, Evelien and Spetea, Mariana and Bracke, Nathalie and Stalmans, Sofie and Betti, Cecilia and Chung, Nga N and Lemieux, Carole and Zuegg, Johannes and Cooper, Matthew A and Tourw{\'e}, Dirk and De Spiegeleer, Bart and Schiller, Peter W and Ballet, Steven},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  keyword      = {TETRAPEPTIDE ANALOGS,METABOLIC STABILITY,PHARMACOLOGICAL CHARACTERIZATION,IN-VITRO,CYCLIC ENKEPHALIN ANALOGS,1 RECEPTOR ANTAGONIST,OPIATE RECEPTOR,AMINO-ACID,PEPTIDE,BRAIN},
  language     = {eng},
  number       = {22},
  pages        = {9549--9561},
  title        = {Variation of the net charge, lipophilicity, and side chain flexibility in Dmt{\textonesuperior}-DALDA: effect on opioid activity and biodistribution},
  url          = {http://dx.doi.org/10.1021/jm3008079},
  volume       = {55},
  year         = {2012},
}

Chicago
Novoa, Alexandre, Sylvia Van Dorpe, Evelien Wynendaele, Mariana Spetea, Nathalie Bracke, Sofie Stalmans, Cecilia Betti, et al. 2012. “Variation of the Net Charge, Lipophilicity, and Side Chain Flexibility in Dmt1-DALDA: Effect on Opioid Activity and Biodistribution.” Journal of Medicinal Chemistry 55 (22): 9549–9561.
APA
Novoa, A., Van Dorpe, S., Wynendaele, E., Spetea, M., Bracke, N., Stalmans, S., Betti, C., et al. (2012). Variation of the net charge, lipophilicity, and side chain flexibility in Dmt1-DALDA: effect on opioid activity and biodistribution. JOURNAL OF MEDICINAL CHEMISTRY, 55(22), 9549–9561.
Vancouver
1.
Novoa A, Van Dorpe S, Wynendaele E, Spetea M, Bracke N, Stalmans S, et al. Variation of the net charge, lipophilicity, and side chain flexibility in Dmt1-DALDA: effect on opioid activity and biodistribution. JOURNAL OF MEDICINAL CHEMISTRY. 2012;55(22):9549–61.
MLA
Novoa, Alexandre, Sylvia Van Dorpe, Evelien Wynendaele, et al. “Variation of the Net Charge, Lipophilicity, and Side Chain Flexibility in Dmt1-DALDA: Effect on Opioid Activity and Biodistribution.” JOURNAL OF MEDICINAL CHEMISTRY 55.22 (2012): 9549–9561. Print.