Synthesis and Biological Evaluation of an Orally Active Glycosylated Endomorphin-1

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 ED(50) of 8.3 (± 0.8) μmol/kg. The corresponding ED(50) for morphine was 2.6 (± 1.4) μmol/kg. Importantly, compound 2 produced dose-dependent pain relief after oral administration in CCI rats (ED(50) = 19.6 (± 1.2) μmol/kg), which was comparable with that of morphine (ED(50) = 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.

In vivo pharmacological evaluation of a lactose-conjugated luteinizing hormone releasing hormone analogue

“…showing that the modification of opioid peptide endomorphin-1 by a lactose moiety resulted in significant analgesic activity of the peptide following oral administration to rats (Varamini et al, 2012). To the best of our knowledge, this is the first report of an orally administered LHRH analogue with a remarkable half-life and bioavailability.…”

New gonadotropin-releasing hormone glycolipids with direct antiproliferative activity and gonadotropin-releasing potency

“…Acetylated, butanoic acid-conjugated carbohydrates were synthesized adapting or following published procedures (Varamini et al, 2012b) as summarized in Scheme 1, and 1 H-NMR spectra matched the published ones (Moradi et al, 2013). Chemical structures are shown in Table 1.…”

“…Peptide analogs with a higher apparent permeability are shown to have better absorption and produce higher plasma peak concentrations compared to those with lower membrane permeability (Varamini et al, 2012b). A Caco-2 cell membrane model was used as a preliminary tool to screen membrane permeability.…”

“…It caused an unprecedented 700-fold increase in membrane permeability of a different peptide (Varamini et al, 2012b).…”

“…Conjugation to carbohydrates has been shown to considerably enhance peptide stability, permeation across biological membranes, and bioavailability (Egleton and Davis, 2005;Varamini et al, 2012b). Lipidation increases the lipophilicity and membrane-like properties of the peptides, thus facilitates their penetration across biological barriers (Griffin, 2011).…”