Lofentanil
Encyclopedia
Lofentanil is one of the most potent opioid
analgesic
s known and is an analogue
of fentanyl, which was developed in 1960. It is most similar to the highly potent opioid carfentanil
(4-carbomethoxyfentanyl), only slightly more potent. Lofentanil can be described as 3-methylcarfentanil, or 3-methyl-4-carbomethoxyfentanyl. While 3-methylfentanyl
is considerably more potent than fentanyl itself, lofentanil is only slightly stronger than carfentanil. This suggests that substitution at both the 3 and 4 positions of the piperidine ring introduces steric hindrance
which prevents μ-opioid
affinity from increasing much further. As with other 3-substituted fentanyl derivatives such as ohmefentanyl
, the stereoisomerism
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. This makes it unsuitable for most practical applications, with carfentanil being the preferred agent for tranquilizing large animals, and short-acting derivatives such as sufentanil
or remifentanil
being preferred for medical use in human surgical procedures. The long duration and high lipophilicity of lofentanil has been suggested as an advantage for certain types of analgesia, but the main application for lofentanil at the present time is research into opiate receptors.
Side effects from lofentanil would be predicted to be similar to other potent fentanyl analogues, and would include sedation
, euphoria
, nausea
, and pronounced itching and respiratory depression. 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 induce tolerance
, due to their high binding affinity triggering rapid internalization of chronically activated opiate receptors. 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 is likely to be especially rapid.
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
s known and is an analogue
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of fentanyl, which was developed in 1960. It is most similar to the highly potent opioid carfentanil
Carfentanil
Carfentanil or carfentanyl is an analogue of the popular synthetic opioid analgesic fentanyl, and is one of the most potent opioids known . Carfentanil was first synthesized in 1974 by a team of chemists at Janssen Pharmaceutica which included Paul Janssen...
(4-carbomethoxyfentanyl), only slightly more potent. Lofentanil can be described as 3-methylcarfentanil, or 3-methyl-4-carbomethoxyfentanyl. While 3-methylfentanyl
3-Methylfentanyl
3-Methylfentanyl is an opioid analgesic that is an analogue of fentanyl. 3-Methylfentanyl is one of the most potent drugs that has been widely sold on the black market, estimated to be between 400-6000 times stronger than morphine depending on which isomer is used .3-Methylfentanyl was first...
is considerably more potent than fentanyl itself, lofentanil is only slightly stronger than carfentanil. This suggests that substitution at both the 3 and 4 positions of the piperidine ring introduces steric hindrance
Steric effects
Steric effects arise from the fact that each atom within a molecule occupies a certain amount of space. If atoms are brought too close together, there is an associated cost in energy due to overlapping electron clouds , and this may affect the molecule's preferred shape and reactivity.-Steric...
which prevents μ-opioid
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...
affinity from increasing much further. As with other 3-substituted fentanyl derivatives such as ohmefentanyl
Ohmefentanyl
Ohmefentanyl was discovered in 1995 and is an extremely potent analgesic drug which selectively binds to the µ-opioid receptor....
, the stereoisomerism
Stereoisomerism
Stereoisomers are isomeric molecules that have the same molecular formula and sequence of bonded atoms , but that differ only in the three-dimensional orientations of their atoms in space. This contrasts with structural isomers, which share the same molecular formula, but the bond connections...
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. This makes it unsuitable for most practical applications, with carfentanil being the preferred agent for tranquilizing large animals, and short-acting derivatives such as sufentanil
Sufentanil
Sufentanil is a powerful synthetic opioid analgesic drug, approximately 5 to 10 times more potent than its analog, fentanyl. Sufentanil is marketed for use by specialist centres under different trade names, such as Sufenta and Sufentil...
or remifentanil
Remifentanil
Remifentanil is a potent ultra short-acting synthetic opioid analgesic drug. It is given to patients during surgery to relieve pain and as an adjunct to an anaesthetic. Remifentanil is used for sedation as well as combined with other medications for use in general anesthesia...
being preferred for medical use in human surgical procedures. The long duration and high lipophilicity of lofentanil has been suggested as an advantage for certain types of analgesia, but the main application for lofentanil at the present time is research into opiate receptors.
Side effects from lofentanil would be predicted to be similar to other potent fentanyl analogues, and would include sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
, euphoria
Euphoria
Euphoria is an emotional and mental state defined as a sense of great elation and well being.Euphoria may also refer to:* Euphoria , a genus of scarab beetles* Euphoria, a genus name previously used for the longan and other trees...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, and pronounced itching and respiratory depression. 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 induce tolerance
Tachyphylaxis
Tachyphylaxis is a medical term describing a decrease in the response to a drug due to previous exposure to that drug. Increasing the dose of the drug may be able to restore the original response. In this context tachyphylaxis is a synonym for drug tolerance...
, due to their high binding affinity triggering rapid internalization of chronically activated opiate receptors. 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 is likely to be especially rapid.