Synthesis, biological activity and structure-activity relationship of endomorphin-1/substance P derivatives

Varamini, Pegah, Hussein, Waleed M., Mansfeld, Friederike M. and Toth, Istvan (2012) Synthesis, biological activity and structure-activity relationship of endomorphin-1/substance P derivatives. Bioorganic & Medicinal Chemistry, 20 21: 6335-6343. doi:10.1016/j.bmc.2012.09.003

Author Varamini, Pegah
Hussein, Waleed M.
Mansfeld, Friederike M.
Toth, Istvan
Title Synthesis, biological activity and structure-activity relationship of endomorphin-1/substance P derivatives
Journal name Bioorganic & Medicinal Chemistry   Check publisher's open access policy
ISSN 0968-0896
Publication date 2012-11-01
Sub-type Article (original research)
DOI 10.1016/j.bmc.2012.09.003
Volume 20
Issue 21
Start page 6335
End page 6343
Total pages 9
Place of publication Oxford, United Kingdom
Publisher Pergamon
Collection year 2013
Language eng
Formatted abstract
Endomorphins have been shown to produce potent analgesia in various rodent models of pain. However, their central administration led to the development of tolerance and physical dependence. Conjugation of C-terminal substance P (SP) fragments to opioids and opioid peptides was previously shown to produce hybrid peptides with strong analgesic activity, with low or no propensity to develop tolerance. In this study, four peptides (2-5) comprised of endomorphin-1 (1) and C-terminal fragments of SP (four or five amino acids, SP 8-11 (2) or SP 7-11 (4), respectively), with an overlapping Phe residue, were synthesized. To overcome low metabolic stability and poor membrane permeability of the peptide, the N-terminus of 2 and 4 was further modified with a C10-carbon lipoamino acid (C10LAA) achieving 3 and 5, respectively. LAA-modification of the hybrid peptides resulted in a significant increase in metabolic stability and membrane permeability compared to peptides 1, 2 and 4. Compound 5 showed potent μ-opioid receptor binding affinity (K iμ = 3.87 ± 0.51 nM) with dose-dependent agonist activity in the nanomolar range (IC 50 = 45 ± 13 nM). In silico modeling was used to investigate the binding modes and affinities of compounds 1-5 in the active site of μ-opioid receptors. The docking scores were in agreement with the K iμ values obtained in the receptor binding affinity studies. The more active LAA-modified hybrid peptide showed a lower total interaction energy and higher negative value of MolDock score.
Keyword Endomorphin 1
Hybrid peptides
Lipoamino acid
Peptide Delivery
Substance P
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Chemistry and Molecular Biosciences
School of Pharmacy Publications
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Created: Fri, 19 Oct 2012, 10:29:26 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences