Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides

Koda, Y., Del Borgo, M., Wessling, S., Lazarus, L. H., Okada, Y., Toth, I. and Blanchfield, J. T. (2008) Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides. Bioorganic & Medicinal Chemistry, 16 11: 6286-6296. doi:10.1016/j.bmc.2008.04.020

Author Koda, Y.
Del Borgo, M.
Wessling, S.
Lazarus, L. H.
Okada, Y.
Toth, I.
Blanchfield, J. T.
Title Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides
Journal name Bioorganic & Medicinal Chemistry   Check publisher's open access policy
ISSN 0968-0896
Publication date 2008-01-01
Year available 2008
Sub-type Article (original research)
DOI 10.1016/j.bmc.2008.04.020
Open Access Status DOI
Volume 16
Issue 11
Start page 6286
End page 6296
Total pages 11
Editor Wong, C.
Waldmann, H.
Hashimoto, Y.
Place of publication United Kingdom
Publisher Pergamon
Language eng
Subject C1
0304 Medicinal and Biomolecular Chemistry
9204 Public Health (excl. Specific Population Health)
Abstract Endomorphin 1 (Endo-1 = Tyr-Pro-Trp-Phe-NH2), an endogenous opioid with high affinity and selectivity for [mu]-opioid receptors, mediates acute and neuropathic pain in rodents. To overcome metabolic instability and poor membrane permeability, the N- and C-termini of Endo-1 were modified by lipoamino acids (Laa) and/or sugars, and 2',6'-dimethyltyrosine (Dmt) replacement of Tyr. Analogues were assessed for [mu]-opioid receptor affinity, inhibition of cAMP accumulation, enzymatic stability, and permeability across Caco-2 cell monolayers. C-Terminus modification decreased receptor affinity, while N-terminus C8-Laa improved stability and permeability with slight change in receptor affinity. Dmt provided a promising lead compound: [C8Laa-Dmt[1]]-Endo-1 is nine times more stable (t1/2 = 43.5 min), >8-fold more permeable in Caco-2 cell monolayers, and exhibits 140-fold greater [mu]-opioid receptor affinity (Ki[mu] = 0.08 nM).
Keyword Endomorphin 1
Opioid peptides
Lipoamino acids
Drug delivery
Oral peptide delivery
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID Z01 ES090053-20
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
School of Pharmacy Publications
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Citation counts: TR Web of Science Citation Count  Cited 41 times in Thomson Reuters Web of Science Article | Citations
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Created: Sat, 04 Apr 2009, 00:59:09 EST by Elizabeth Pyke on behalf of School of Pharmacy