Synthesis and biological evaluation of an orally active glycosylated endomorphin-1.
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.
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
Pegah
P
Varamini
Friederike M
FM
Mansfeld
Joanne T
JT
Blanchfield
Bruce D
BD
Wyse
Maree T
MT
Smith
Istvan
I
Toth
D000042:Absorption; D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D060326:Chemistry Techniques, Synthetic; D003248:Constipation / Q000139:chemically induced; D006224:Cricetinae; D003412:Cricetulus; D006031:Glycosylation; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists; D009437:Neuralgia / Q000188:drug therapy; D009842:Oligopeptides / Q000009:adverse effects / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009842:Oligopeptides; D011957:Receptors, Opioid; C105293:endomorphin 1; D009270:Naloxone