Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Lofentanil: Difference between pages

{{Short description|Opioid analgesic}}

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| image2 = Lofentanil molecule ball.png

| width2 = 170

| legal_US = Schedule II (fentanyl analogue; [[Federal Analogue Act]])

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| CAS_number_Ref = {{cascite||??}}

| CAS_number = 61380-40-3

| UNII_Ref = {{fdacite||FDA}}

| ChEMBL_Ref = {{ebicite||EBI}}

| smiles = O=(CC)N(c1ccccc1)[C@@]2(C(OC)=O)CCN(C[C@H]2C)CCc3ccccc3

| synonyms = Lofentanil; <small>methyl (3''S'',4''R'')-1-(2-)-4 -(-propanoylamino)-3-methylpiperidine-4-carboxylate</small>

'''Lofentanil''' or '''lofentanyl''' is one of the most potent [[opioid]] [[analgesic]]s known and is an [[analog (chemistry)|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]].<ref>{{cite journal | vauthors = Gommeren W, Leysen JE | date = Jul 1982 | title = Binding properties of 3H-lofentanil at the opiate receptor | journal = Archives Internationales de Pharmacodynamie et de Thérapie | volume = 258 | issue = 1| pages = 171–3 | pmid = 6291471 }}</ref><ref>{{cite journal | vauthors = Meert TF, Lu HR, van Craenndonck H, Janssen PA | title = Comparison between epidural fentanyl, sufentanil, carfentanil, lofentanil and alfentanil in the rat: analgesia and other in vivo effects | journal = European Journal of Anaesthesiology | volume = 5 | issue = 5 | pages = 313–21 | date = September 1988 | pmid = 2905988 }}</ref> This suggests that substitution at both the 3 and 4 positions of the [[piperidine]] ring introduces [[Steric effects|steric hindrance]] which prevents [[Mu opioid receptor|μ-opioid]] [[dissociation constant#Protein-ligand binding|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.<ref>{{cite journal | vauthors = Laduron PM, Janssen PF | title = Axoplasmic transport and possible recycling of opiate receptors labelled with 3H-lofentanil | journal = Life Sciences | volume = 31 | issue = 5 | pages = 457–62 | date = August 1982 | pmid = 6182434 | doi = 10.1016/0024-3205(82)90331-9 }}</ref> 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,<ref>{{cite journal | vauthors = Foldes FF | title = Pain control with intrathecally and peridurally administered opioids and other drugs | journal = Anaesthesiologie und Reanimation | volume = 16 | issue = 5 | pages = 287–98 | year = 1991 | pmid = 1683773 }}</ref> but the main application for lofentanil at the present time is research into opioid receptors.<ref>{{cite journal | vauthors = Maguire P, Tsai N, Kamal J, Cometta-Morini C, Upton C, Loew G | title = Pharmacological profiles of fentanyl analogs at mu, delta and kappa opiate receptors | journal = European Journal of Pharmacology | volume = 213 | issue = 2 | pages = 219–25 | date = March 1992 | pmid = 1355735 | doi = 10.1016/0014-2999(92)90685-w }}</ref><ref>{{cite journal | vauthors = Huang XQ, Jiang HL, Luo XM, Chen KX, Zhu YC, Ji RY, Cao Y | title = Study on mechanism of interaction of nociceptin and opioids binding with opioid receptor-like 1 receptor | journal = Acta Pharmacologica Sinica | volume = 21 | issue = 6 | pages = 536–46 | date = June 2000 | pmid = 11360688 }}</ref> Its potency has led some to compare it to [[Nerve agent|nerve agents]] as a chemical weapon since carfentanil's use in the [[Moscow hostage crisis]].

Side effects of lofentanyl analogs are similar to those of fentanyl itself, which include [[itching]], [[nausea]], and potentially serious [[respiratory depression]], which can be life-threatening. Fentanyl analogs have killed hundreds 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.<ref>{{cite journal | vauthors = Mounteney J, Giraudon I, Denissov G, Griffiths P | title = Fentanyls: Are we missing the signs? Highly potent and on the rise in Europe | journal = The International Journal on Drug Policy | volume = 26 | issue = 7 | pages = 626–31 | date = July 2015 | pmid = 25976511 | doi = 10.1016/j.drugpo.2015.04.003 }}</ref> 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 [[Tachyphylaxis|tolerance]], due to their high binding affinity triggering rapid internalization of chronically activated opiate receptors.<ref>{{cite journal | vauthors = Bot G, Blake AD, Li S, Reisine T | title = Fentanyl and its analogs desensitize the cloned mu opioid receptor | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 285 | issue = 3 | pages = 1207–18 | date = June 1998 | pmid = 9618424 }}</ref> 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 the [[μ-opioid receptor]], lofentanil has also been found to act as a [[full agonist]] of the [[κ-opioid receptor]] (K_i = 8.2 nM; [[EC50|EC₅₀]] = 153 nM; [[intrinsic activity|E_max]] = 100%).<ref name="GharagozlouHashemi2006">{{cite journal | vauthors = Gharagozlou P, Hashemi E, DeLorey TM, Clark JD, Lameh J | title = Pharmacological profiles of opioid ligands at kappa opioid receptors | journal = BMC Pharmacology | volume = 6 | issue = 1 | pages = 3 | date = January 2006 | pmid = 16433932 | pmc = 1403760 | doi = 10.1186/1471-2210-6-3 | doi-access = free }}</ref>

==See also==

* [[Equianalgesic|Opioid potency comparison]]

== References ==

{{Reflist|2}}

{{Opioidergics}}

[[Category:Synthetic opioids]]

[[Category:Piperidines]]

[[Category:Carboxylate esters]]

[[Category:Anilines]]

[[Category:Propionamides]]

[[Category:Mu-opioid receptor agonists]]

[[Category:Janssen Pharmaceutica]]

[[Category:Kappa-opioid receptor agonists]]

[[Category:Fentanyl]]