73232-52-7

The widespread efficacy of opioids in treating patients with moderate to severe acute and chronic pain is often accompanied by untoward side effects. In particular, opioid-induced bowel dysfunction is one of the more common and debilitating consequences afflicting up to 50% of patients. To counteract the peripherally-mediated adverse effects, opioid antagonists such as naloxone, naltrexone, and nalmephene are sometimes prescribed. The latest market entry exploits a strategic modification of naltrexone to lower its lipid solubility and increase its polarity: quaternization of the amine of naltrexone by methylation (methyl bromide) prevents crossing of the blood–brain barrier thereby creating an effective peripheral antagonist. Despite a loss of potency upon methylation, methylnaltrexone antagonizes opioid binding at m-opioid receptors with an IC₅₀ of 70 nM. Its affinity for k-opioid receptors is approximately eightfold less (IC₅₀＝ 575 nM) with no significant binding to d-opioid, orphanin, or non-opioid receptors. Methylnaltrexone bromide has been approved for the treatment of opioid-induced constipation in patients with advanced illness receiving palliative care.Regarding metabolism, methylnaltrexone bromide is eliminated primarily as intact drug (85% based on administered radioactivity) by slightly more renal than hepatic clearance.
The most common adverse events were abdominal pain and flatulence followed by nausea, dizziness, and diarrhea.

Pale Pink Solid

University of Chicago (United States)

A metabolite of Naltrexone (N285750). Methylnaltrexone (MNTX), a selective μ-opioid receptor antagonist, functions as a peripherally acting receptor antagonist in tissues of the gastrointestinal tract.

Relistor

Methylnaltrexone bromide is a narcotic antagonist. It is a peripheral mu-opiod receptor antagonist that cannot cross the blood-brain barrier. It reverses many opioid side-effects without interfering with pain relief.

N-Methylnaltrexone is the polar derivative of naltrexone, which does not reach the central nervous system but can block intestinal opioid receptors. The compound is under development to counteract opioid induced bowel dysfunction such as constipation and megacolon .

The synthesis of methylnaltrexone bromide proceeds in a straightforward manner via the alkylation of naltrexone 90 in the following scheme. Naltrexone 90 was reacted with methyl bromide in 1-methyl-2-pyrrolidinone at 60 ??C. The resulting crude product was treated with sodium methoxide in methanol/ water at 55 ??C to remove any undesired phenolic (Oalkylated) side-products. The resulting crude sodium salt was treated with hydrobromic acid in methanol/water and upon crystallization gave methylnaltrexone bromide (XII) in 35% overall yield.

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