| Revision as of 16:38, 3 December 2010 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers from ChemSpider, CommonChemistry and FDA for the Chem/Drugbox validation project - Updated: InChI1->InChI StdInChI StdInChIKey.← Previous edit |
Latest revision as of 18:43, 21 October 2024 edit undoJWBE (talk | contribs)Extended confirmed users10,111 edits removed Category:Phenols; added Category:3-Hydroxyphenyl compounds using HotCat |
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{{Short description|Opioid painkiller medication}} |
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{{DISPLAYTITLE:''O''-Desmethyltramadol}} |
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{{Drugbox |
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{{drugbox | |
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| Verifiedfields = changed |
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| IUPAC_name = 3-phenol |
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| Watchedfields = changed |
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| image = O-Desmethyltramadol.png |
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| verifiedrevid = 400334182 |
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| width = 160 |
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| IUPAC_name = 3-(2-((dimethylamino)methyl)-1-hydroxycyclohexyl)phenol |
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| ChemSpiderID = 115703 |
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| image = O-desmethyltramadol racemate2DCSD3.svg |
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| InChI = 1/C15H23NO2/c1-16(2)11-13-6-3-4-9-15(13,18)12-7-5-8-14(17)10-12/h5,7-8,10,13,17-18H,3-4,6,9,11H2,1-2H3 |
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| width = 250px |
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| InChIKey = UWJUQVWARXYRCG-UHFFFAOYAM |
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| StdInChI = 1S/C15H23NO2/c1-16(2)11-13-6-3-4-9-15(13,18)12-7-5-8-14(17)10-12/h5,7-8,10,13,17-18H,3-4,6,9,11H2,1-2H3 |
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<!--Clinical data--> |
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| StdInChIKey = UWJUQVWARXYRCG-UHFFFAOYSA-N |
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| tradename = |
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| CAS_number = 73986-53-5 |
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| ATC_prefix = |
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| pregnancy_AU = |
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| ATC_suffix = |
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| PubChem = 130829 |
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| C=15 | H=23 | N=1 | O=2 |
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| molecular_weight = 249.349 g/mol |
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| smiles = OC2(c1cc(O)ccc1)CCCCC2CN(C)C |
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| melting_point = |
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| bioavailability = |
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| protein_bound = |
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| metabolism = |
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| elimination_half-life = ~ 9 h |
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| excretion = |
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| pregnancy_AU = |
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| pregnancy_US = |
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| pregnancy_category = |
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| pregnancy_category = |
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| legal_AU = |
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| legal_AU = |
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| legal_CA = |
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| legal_US = Unscheduled |
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| legal_status = |
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| legal_status = |
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| routes_of_administration = Orally Converted Metabolite, Oral, Insufflation, Rectal, IV |
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| routes_of_administration = |
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<!--Pharmacokinetic data--> |
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| bioavailability = |
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| protein_bound = |
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| metabolism = ] and ]<ref>, PharmGKB</ref> |
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| elimination_half-life = 6-8 hours |
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| excretion = |
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<!--Identifiers--> |
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| CAS_number_Ref = {{cascite|changed|CAS}} |
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| CAS_number = 80456-81-1 |
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| ATC_prefix = |
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| ATC_suffix = |
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| PubChem = 130829 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 115703 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = 1400 |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII = 2WA8F50C3F |
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| synonyms = ''O''-Desmethyltramadol; ''O''-DSMT; Omnitram |
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<!--Chemical data--> |
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| C=15 | H=23 | N=1 | O=2 |
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| SMILES = OC2(c1cc(O)ccc1)CCCCC2CN(C)C |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C15H23NO2/c1-16(2)11-13-6-3-4-9-15(13,18)12-7-5-8-14(17)10-12/h5,7-8,10,13,17-18H,3-4,6,9,11H2,1-2H3 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = UWJUQVWARXYRCG-UHFFFAOYSA-N |
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}} |
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'''Desmetramadol''' ({{abbrlink|INN|International Nonproprietary Name}}), also known as '''''O''-desmethyltramadol''' ('''''O''-DSMT'''), is an ] ] and the main ] of ].<ref name="pmid8220877">{{cite journal | vauthors = Sevcik J, Nieber K, Driessen B, Illes P | title = Effects of the central analgesic tramadol and its main metabolite, O-desmethyltramadol, on rat locus coeruleus neurones | journal = British Journal of Pharmacology | volume = 110 | issue = 1 | pages = 169–76 | date = September 1993 | pmid = 8220877 | pmc = 2175982 | doi = 10.1111/j.1476-5381.1993.tb13788.x }}</ref> Tramadol is demethylated by the ] enzyme ]<ref name="pmid14624403">{{cite journal | vauthors = Borlak J, Hermann R, Erb K, Thum T | title = A rapid and simple CYP2D6 genotyping assay--case study with the analgetic tramadol | journal = Metabolism | volume = 52 | issue = 11 | pages = 1439–43 | date = November 2003 | pmid = 14624403 | doi = 10.1016/s0026-0495(03)00256-7 }}</ref> to desmetramadol in the same way as ], and so similarly to the variation in effects seen with codeine, individuals who have a less active form of CYP2D6 will tend to have reduced analgesic effects from tramadol. Because desmetramadol itself does not need to be metabolized to induce an analgesic effect, it can be used in individuals with low CYP2D6 activity unlike tramadol. |
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'''''O''-Desmethyltramadol''' is an ] ] and the main ] of ].<ref>{{cite pmid|8220877}}</ref> |
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==Pharmacology== |
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(+)-''O''-Desmethyltramadol is the most important ] of ] produced in the ] after tramadol is consumed. This metabolite is considerably more potent as a ] ] than the parent compound,<ref>{{cite pmid|9190321}}</ref>. |
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===Pharmacodynamics=== |
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Tramadol is demethylated by the liver enzyme ]<ref>{{cite pmid|14624403}}</ref> in the same way as codeine, and so similarly to the variation in effects seen with codeine, individuals who have a less active form of CYP2D6 ("poor metabolisers") will tend to get reduced analgesic effects from tramadol. |
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(+)-Desmetramadol is a G-protein biased ] full ].<ref name="pmid32116679">{{cite journal | vauthors = Zebala JA, Schuler AD, Kahn SJ, Maeda DY | title = Desmetramadol Is Identified as a G-Protein Biased µ Opioid Receptor Agonist | journal = Frontiers in Pharmacology | volume = 10 | pages = 1680 | date = 2019 | pmid = 32116679 | pmc = 7025522 | doi = 10.3389/fphar.2019.01680 | doi-access = free }}</ref> It shows comparatively far lower affinity for the ] and ]s.<ref name="pmid10991912">{{cite journal | vauthors = Potschka H, Friderichs E, Löscher W | title = Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy | journal = British Journal of Pharmacology | volume = 131 | issue = 2 | pages = 203–12 | date = September 2000 | pmid = 10991912 | pmc = 1572317 | doi = 10.1038/sj.bjp.0703562 }}</ref> |
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The two enantiomers of desmetramadol show quite distinct pharmacological profiles;<ref name="pmid10992001">{{cite journal | vauthors = Garrido MJ, Valle M, Campanero MA, Calvo R, Trocóniz IF | title = Modeling of the in vivo antinociceptive interaction between an opioid agonist, (+)-O-desmethyltramadol, and a monoamine reuptake inhibitor, (-)-O-desmethyltramadol, in rats | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 295 | issue = 1 | pages = 352–9 | date = October 2000 | pmid = 10992001 }}</ref> both (+) and (−)-desmetramadol are inactive as ]s,<ref name="pmid9389855">{{cite journal | vauthors = Bamigbade TA, Davidson C, Langford RM, Stamford JA | title = Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus | journal = British Journal of Anaesthesia | volume = 79 | issue = 3 | pages = 352–6 | date = September 1997 | pmid = 9389855 | doi = 10.1093/bja/79.3.352 | doi-access = free }}</ref> but (−)-desmetramadol retains activity as a ],<ref name="pmid8467366">{{cite journal | vauthors = Driessen B, Reimann W, Giertz H | title = Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro | journal = British Journal of Pharmacology | volume = 108 | issue = 3 | pages = 806–11 | date = March 1993 | pmid = 8467366 | pmc = 1908052 | doi = 10.1111/j.1476-5381.1993.tb12882.x }}</ref> and so the mix of both the parent compound and metabolites contributes significantly to the complex pharmacological profile of tramadol. While the multiple receptor targets can be beneficial in the treatment of pain (especially complex pain syndromes such as neuropathic pain), it increases the potential for ] compared to other opioids, and may also contribute to ]s. |
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The two enantiomers of ''O''-desmethyltramadol show quite distinct pharmacological profiles;<ref>{{cite pmid|10992001}}</ref> both (+) and (-)-''O''-desmethyltramadol are inactive as serotonin reuptake inhibitors,<ref>{{cite pmid|9389855}}</ref> but (-)-''O''-desmethyltramadol retains activity as a noradrenaline reuptake inhibitor<ref>{{cite pmid|8467366}}</ref> and so the mix of both the parent compound and metabolites produced contributes significantly to the complex pharmacological profile of tramadol. |
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Desmetramadol is also an ] of the ] ], at pharmacologically relevant concentrations, via competitive inhibition.<ref name="pmid16679816">{{cite journal | vauthors = Horishita T, Minami K, Uezono Y, Shiraishi M, Ogata J, Okamoto T, Shigematsu A | title = The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus Oocytes | journal = Pharmacology | volume = 77 | issue = 2 | pages = 93–9 | year = 2006 | pmid = 16679816 | doi = 10.1159/000093179 | s2cid = 23775035 }}</ref> This suggests that the apparent anti-depressant properties of tramadol may be at least partially mediated by desmetramadol, thus prolonging the duration of therapeutic benefit. |
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==References== |
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Inhibition of the ] receptor is a suggested factor in the mechanism of anti-depressant effects of ] and ]. The potential selectivity and favorable side effect profile of desmetramadol compared to its prodrug, ], makes it more suitable for clinical use, although no such large scale controlled trials have been conducted with patients. |
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Upon inhibition of the receptor, downstream signaling causes ] and ] release, and the receptor is thought to significantly regulate mood, anxiety, feeding, and reproductive behavior. 5-HT<sub>2C</sub> receptors regulate dopamine release in the ], ], ], ], ], and ], among others.<ref name="pmid17451451">{{cite journal | vauthors = Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH | title = Serotonin 5-HT(2C) receptors regulate anxiety-like behavior | journal = Genes, Brain and Behavior | volume = 6 | issue = 5 | pages = 491–6 | date = July 2007 | pmid = 17451451 | doi = 10.1111/j.1601-183X.2007.00316.x | s2cid = 143950479 | doi-access = free }}</ref> |
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Research indicates that some suicide victims have an abnormally high number of 5-HT<sub>2C</sub> receptors in the prefrontal cortex.<ref name="pmid11282248">{{cite journal | vauthors = Niswender CM, Herrick-Davis K, Dilley GE, Meltzer HY, Overholser JC, Stockmeier CA, Emeson RB, Sanders-Bush E | display-authors = 6 | title = RNA editing of the human serotonin 5-HT2C receptor. alterations in suicide and implications for serotonergic pharmacotherapy | journal = Neuropsychopharmacology | volume = 24 | issue = 5 | pages = 478–91 | date = May 2001 | pmid = 11282248 | doi = 10.1016/S0893-133X(00)00223-2 | doi-access = free }}</ref> There is some mixed evidence that ], a 5-HT<sub>2C</sub> ], is an effective ].<ref name="pmid20694073">{{cite journal | vauthors = Eser D, Baghai TC, Möller HJ | title = Agomelatine: The evidence for its place in the treatment of depression | journal = Core Evidence | volume = 4 | pages = 171–9 | date = June 2010 | pmid = 20694073 | pmc = 2899775 | doi = 10.2147/CE.S6005 | doi-access = free }}</ref> Antagonism of 5-HT<sub>2C</sub> receptors by agomelatine results in an increase of dopamine and norepinephrine activity in the frontal cortex. |
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===Pharmacokinetics=== |
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====Metabolites==== |
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Desmetramadol is metabolized in the liver into the active metabolite ''N'',''O''-didesmethyltramadol via ] and ]. The inactive tramadol metabolite ''N''-desmethyltramadol is metabolized into the active metabolite ] by ]. |
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== History == |
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{{Unreferenced section|date=August 2023}} |
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The history of desmetramadol is intrinsically linked to its discovery and development within the pharmaceutical industry. This journey begins with its synthesis in the research laboratories of ], a prominent pharmaceutical establishment based in Germany, during the late 1970s. |
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This innovative synthesis marked the inception of desmetramadol as a pharmacological entity. While tramadol, its precursor, was introduced to the global pharmaceutical market in the early 1980s under various brand names and gained adoption as a pain-relieving medication notable for its dual-action characteristics, desmetramadol emerged as a significant metabolite derived from tramadol's metabolism. |
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In the realm of pharmacology, desmetramadol garnered attention for its unique pharmacological profile. Researchers and healthcare professionals recognized its distinct properties and utility. This recognition proved particularly crucial in cases where tramadol's effectiveness was influenced by individual variations in ] enzyme activity. Today, desmetramadol stands as a noteworthy component of the pharmaceutical landscape, offering valuable insights into pain management and pharmacogenetics. |
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==Society and culture== |
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===Recreational use=== |
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Desmetramadol has been sold in a blend called ''Krypton'' and marketed as powdered ] leaf (''Mitragyna speciosa''). ''Krypton'' was reportedly linked to at least 9 accidental deaths from ] in ] during 2010–2011.<ref name="pmid21112167">{{cite journal | vauthors = Arndt T, Claussen U, Güssregen B, Schröfel S, Stürzer B, Werle A, Wolf G | title = Kratom alkaloids and O-desmethyltramadol in urine of a "Krypton" herbal mixture consumer | journal = Forensic Science International | volume = 208 | issue = 1–3 | pages = 47–52 | date = May 2011 | pmid = 21112167 | doi = 10.1016/j.forsciint.2010.10.025 }}</ref><ref>{{cite journal | vauthors = Bäckstrom BG, Classon G, Löwenhielm P, Thelander G | title = | journal = Läkartidningen | volume = 107 | issue = 50 | pages = 3196–7 | year = 2010 | pmid = 21294331 }}</ref><ref name="pmid21513619">{{cite journal | vauthors = Kronstrand R, Roman M, Thelander G, Eriksson A | title = Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton | journal = Journal of Analytical Toxicology | volume = 35 | issue = 4 | pages = 242–7 | date = May 2011 | pmid = 21513619 | doi = 10.1093/anatox/35.4.242 | doi-access = free }}</ref> |
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===Medicinal use=== |
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Unusually for a compound that first came to prominence as a recreational ], desmetramadol has recently been reevaluated as a potential novel ] drug for use in medicine, with its well studied pharmacology and toxicology as an active metabolite of the widely used analgesic drug tramadol offering advantages over more structurally novel alternatives. Human ]s have shown it to offer similar analgesic benefits to drugs such as ] and ] but with reduced respiratory depression and a comparatively favorable safety profile.<ref name="pmid31005596">{{cite journal | vauthors = Zebala JA, Searle SL, Webster LR, Johnson MS, Schuler AD, Maeda DY, Kahn SJ | title = Desmetramadol Has the Safety and Analgesic Profile of Tramadol Without Its Metabolic Liabilities: Consecutive Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Trials | journal = The Journal of Pain | volume = 20 | issue = 10 | pages = 1218–1235 | date = October 2019 | pmid = 31005596 | pmc = 6790288 | doi = 10.1016/j.jpain.2019.04.005 | url = }}</ref><ref name="pmid32116679" /> |
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===Legality=== |
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====United Kingdom==== |
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Desmetramadol was made a Class A drug in the United Kingdom on 26 Feb 2013.<ref name="2013 Misuse of drugs Amendment ">{{Cite web |url=http://www.legislation.gov.uk/uksi/2013/177/made |title=The Misuse of Drugs (Designation) (Amendment) (England, Wales and Scotland) Order 2013 |date=31 January 2013 |publisher=UK Home Office}}</ref> |
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== See also == |
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* ] |
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* ] |
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* ] |
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* ] |
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* ] |
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== References == |
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{{Reflist|2}} |
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{{Reflist|2}} |
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{{Monoamine reuptake inhibitors}} |
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{{Opioids}} |
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{{Opioid receptor modulators}} |
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{{Serotonin receptor modulators}} |
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{{DEFAULTSORT:Desmethyltramadol, O-}} |
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{{DEFAULTSORT:Desmethyltramadol, O-}} |
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