Peripherally acting novel lipo-endomorphin-1 peptides in neuropathic pain without producing constipation

Varamini, Pegah, Goh, Wei Huang, Mansfeld, Friederike M., Blanchfield, Joanne T., Wyse, Bruce D., Smith, Maree T. and Toth, Istvan (2013) Peripherally acting novel lipo-endomorphin-1 peptides in neuropathic pain without producing constipation. Bioorganic & Medicinal Chemistry, 21 7: 1898-1904. doi:10.1016/j.bmc.2013.01.044


Author Varamini, Pegah
Goh, Wei Huang
Mansfeld, Friederike M.
Blanchfield, Joanne T.
Wyse, Bruce D.
Smith, Maree T.
Toth, Istvan
Title Peripherally acting novel lipo-endomorphin-1 peptides in neuropathic pain without producing constipation
Journal name Bioorganic & Medicinal Chemistry   Check publisher's open access policy
ISSN 0968-0896
1464-3391
Publication date 2013-04
Sub-type Article (original research)
DOI 10.1016/j.bmc.2013.01.044
Volume 21
Issue 7
Start page 1898
End page 1904
Total pages 7
Place of publication Kidlington, Oxford, United Kingdom
Publisher Pergamon
Collection year 2014
Language eng
Abstract We previously described two novel analogues of endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, 1), modified with an 8-carbon lipoamino acid (C8LAA) with or without replacement of Tyr1 with 2,6-dimethyltyrosine (Dmt) at the N-terminus of the peptide (compounds 3 and 4, respectively). They were shown to be more stable and permeable, and acted as potent μ-opioid receptor agonists. In this study we report that the C8LAA modification resulted in successful systemic delivery of both analogues. They produced potent dose-dependent pain relief in a chronic constriction injury-rat model of neuropathic pain after intravenous administration with ED50 values obtained at 6.58 (±1.22) μmol/kg for 3 and 6.18 (±1.17) μmol/kg for 4. Using two different rat models of constipation that assess the effects of μ-opioid receptor agonists on stool hydration and gastro-intestinal motility, compound 3 produced insignificant constipation at 16 μmol/kg, whereas morphine elicited significant constipation at 2 μmol/kg. Compound 3 in contrast to morphine, did not attenuate the hypercapnic ventilatory response at 5 μmol/kg, a dose that fully alleviated hindpaw sensitivity at the time of peak effect in CCI-rats. This finding revealed the lack of respiratory depression effect at antinociceptive dose.
Keyword Endomorphin-1
Peptide delivery
Lipoamino acid
Constipation
Neuropathic pain
Respiratory depression
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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