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

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Varamini P, Mansfeld FM, Blanchfield JT, Wyse BD, Smith MT, Toth I

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

J Med Chem. 2012 Jun 28;55(12):5859-67. doi: 10.1021/jm300418d. Epub 2012 Jun 15.

PubMed ID

22680612 [ View in PubMed

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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 mu-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) mumol/kg. The corresponding ED(50) for morphine was 2.6 (+/- 1.4) mumol/kg. Importantly, compound 2 produced dose-dependent pain relief after oral administration in CCI rats (ED(50) = 19.6 (+/- 1.2) mumol/kg), which was comparable with that of morphine (ED(50) = 20.7 (+/-3.6) mumol/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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Morphine	Kappa-type opioid receptor	Ki (nM)	13.3	N/A	N/A	Details
Morphine	Mu-type opioid receptor	Ki (nM)	0.14	N/A	N/A	Details