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| Other names | Lofentanil;methyl (3S,4R)-1-(2-phenylethyl)-4 -(phenyl-propanoylamino)-3-methylpiperidine-4-carboxylate |
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| Formula | C25H32N2O3 |
| Molar mass | 408.542 g·mol−1 |
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Lofentanil orlofentanyl is one of the most potentopioidanalgesics known and is ananalogue offentanyl, which was developed in 1960. It is most similar to the highly potent opioidcarfentanil (4-carbomethoxyfentanyl), only slightly more potent. Lofentanil can be described as 3-methylcarfentanil, or 3-methyl-4-carbomethoxyfentanyl. While3-methylfentanyl is considerably more potent than fentanyl itself, lofentanil is only slightly stronger thancarfentanil.[1][2] This suggests that substitution at both the 3 and 4 positions of thepiperidine ring introducessteric hindrance which preventsμ-opioidaffinity from increasing much further. As with other 3-substituted fentanyl derivatives such asohmefentanyl, thestereoisomerism of lofentanil is very important, with some stereoisomers being much more potent than others.
Lofentanil is very similar to carfentanil in effects, but has a longer duration of action.[3] This makes it unsuitable for most practical applications, with carfentanil being the preferred agent for tranquilizing large animals, and short-acting derivatives such assufentanil orremifentanil being preferred for medical use in human surgical procedures. The long duration and highlipophilicity of lofentanil has been suggested as an advantage for certain types of analgesia,[4] but the main application for lofentanil at the present time is research into opioid receptors.[5][6] Its potency has led some to compare it tonerve agents as a chemical weapon since carfentanil's use in theMoscow hostage crisis.
Side effects of lofentanyl analogs are similar to those of fentanyl itself, which includeitching,nausea, and potentially seriousrespiratory depression, which can be life-threatening. Fentanyl analogs have killed hundreds to thousands of people throughout Europe and the former Soviet republics since the most recent resurgence in use began in Estonia in the early 2000s, and novel derivatives continue to appear.[7] Side effects from lofentanil might be particularly problematic given its reportedly long duration of action. Another side effect which is characteristic of fentanyl and its derivatives is their tendency to rapidly inducetolerance, due to their high binding affinity triggering rapid internalization of chronically activated opiate receptors.[8] This might be expected to be a particular problem with lofentanil as it is not only one of the most potent drugs in the series, but also is longer acting than most other fentanyl analogues, meaning that development of tolerance triggered by receptor over-activation could be rapid.
In addition to acting on theμ-opioid receptor, lofentanil has also been found to act as afull agonist of theκ-opioid receptor (Ki = 8.2 nM;EC50 = 153 nM;Emax = 100%).[9]