Synthesis and biological evaluation of an orally active glycosylated endomorphin-1

Varamini, Pegah, Mansfeld, Friederike M., Blanchfield, Joanne T., Wyse, Bruce D., Smith, Maree T. and Toth, Istvan (2012) Synthesis and biological evaluation of an orally active glycosylated endomorphin-1. Journal of Medicinal Chemistry, 55 12: 5859-5867. doi:10.1021/jm300418d

Author Varamini, Pegah
Mansfeld, Friederike M.
Blanchfield, Joanne T.
Wyse, Bruce D.
Smith, Maree T.
Toth, Istvan
Title Synthesis and biological evaluation of an orally active glycosylated endomorphin-1
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 2012-06-28
Sub-type Article (original research)
DOI 10.1021/jm300418d
Volume 55
Issue 12
Start page 5859
End page 5867
Total pages 9
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Formatted abstract
The endogenous opioid peptide endomorphin-1 (1) was modified by attachment of lactose to the N-terminus via a succinamic acid spacer to produce compound 2. The carbohydrate modification significantly improved the metabolic stability and membrane permeability of 2 while retaining μ-opioid receptor binding affinity and agonist activity. Analogue 2 produced dose-dependent antinociceptive activity following intravenous administration in a chronic constriction injury (CCI) rat model of neuropathic pain with an ED50 of 8.3 (±0.8) μmol/kg. The corresponding ED50 for morphine was 2.6 (±1.4) μmol/kg. Importantly, compound 2 produced dose-dependent pain relief after oral administration in CCI rats (ED50 = 19.6 (±1.2) μmol/kg), which was comparable with that of morphine (ED50 = 20.7 (±3.6) μmol/kg). Antineuropathic effects of analogue 2 were significantly attenuated by pretreatment of animals with the opioid antagonist naloxone, confirming opioid receptor-mediated analgesia. In contrast to morphine, no significant constipation was produced by compound 2 after oral administration.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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Created: Fri, 06 Jul 2012, 21:25:47 EST by Lucy O'Brien on behalf of School of Chemistry & Molecular Biosciences