Lipo-endomorphin-1 derivatives with systemic activity against neuropathic pain without producing constipation

Varamini, Pegah, Mansfeld, Friederike M., Blanchfield, Joanne T., Wyse, Bruce D., Smith, Maree T. and Toth, Istvan (2012) Lipo-endomorphin-1 derivatives with systemic activity against neuropathic pain without producing constipation. PLoS One, 7 8 Article. No.e41909: . doi:10.1371/journal.pone.0041909


Author Varamini, Pegah
Mansfeld, Friederike M.
Blanchfield, Joanne T.
Wyse, Bruce D.
Smith, Maree T.
Toth, Istvan
Title Lipo-endomorphin-1 derivatives with systemic activity against neuropathic pain without producing constipation
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2012-08-17
Sub-type Article (original research)
DOI 10.1371/journal.pone.0041909
Open Access Status DOI
Volume 7
Issue 8 Article. No.e41909
Total pages 11
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Collection year 2013
Language eng
Formatted abstract
To enhance the drug-like properties of the endogenous opioid peptide endomorphin-1 (1 = Tyr-Pro-Trp-Phe-NH2), the Nterminus of the peptide was modified with 2-aminodecanoic acid, resulting in compound 3. Tyr in compound 1 was replaced with 2,6-dimethyltyrosine yielding compound 2. Derivative 2 was also substituted with 2-aminodecanoic acid producing compound, 4. Lipoamino acid-modified derivatives showed improved metabolic stability and membrane permeability while maintaining high m-opioid (MOP) receptor binding affinity and acting as a potent agonist. In vivo studies showed dose-dependent antinociceptive activity following intravenous (i.v.) administration of compounds 3 and 4 in a chronic constriction injury (CCI)-rat model of neuropathic pain with ED50 values of 1.22 (60.93) and 0.99 (60.89) mmol/kg,
respectively. Pre-treatment of animals with naloxone hydrochloride significantly attenuated the anti-neuropathic effects of compound 3, confirming the key role of opioid receptors in mediating antinociception. In contrast to morphine, no significant constipation was produced following i.v. administration of compound 3 at 16 mmol/kg. Furthermore, following chronic administration of equi-potent doses of compound 3 and morphine to rats, there was less antinociceptive tolerance for compound 3 compared with morphine.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Received March 29, 2012; Accepted June 28, 2012; Published August 17, 2012

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Chemistry and Molecular Biosciences
School of Pharmacy Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 17 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 18 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Fri, 28 Sep 2012, 15:31:32 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences