Desmetramadol

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Desmetramadol
O-desmethyltramadol racemate2DCSD3.svg
Clinical data
Other namesO-Desmethyltramadol; O-DSMT; Omnitram
Pharmacokinetic data
MetabolismCYP3A4 and CYP2B6[1]
Elimination half-life6-8 hours
Identifiers
  • 3-(2-((dimethylamino)methyl)-1-hydroxycyclohexyl)phenol
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC15H23NO2
Molar mass249.354 g·mol−1
3D model (JSmol)
  • OC2(c1cc(O)ccc1)CCCCC2CN(C)C
  • InChI=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 checkY
  • Key:UWJUQVWARXYRCG-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Desmetramadol (INN), also known as O-desmethyltramadol (O-DSMT), is an opioid analgesic and the main active metabolite of tramadol.[2] Tramadol is demethylated by the liver enzyme CYP2D6[3] 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 metabolizers") will tend to get reduced analgesic effects from tramadol. This also results in a ceiling effect (dependent on CYP2D6 availability) which limits tramadol's range of therapeutic benefits to the treatment of moderate pain.

Pharmacology[edit]

Pharmacodynamics[edit]

(+)-Desmetramadol is a G-protein biased μ-opioid receptor full agonist.[4] It shows comparatively far lower affinity for the δ- and κ-opioid receptors.[5]

The two enantiomers of desmetramadol show quite distinct pharmacological profiles;[6] both (+) and (−)-desmetramadol are inactive as serotonin reuptake inhibitors,[7] but (−)-desmetramadol retains activity as a norepinephrine reuptake inhibitor,[8] 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 drug interactions compared to other opioids, and may also contribute to side effects.

Desmetramadol is also an antagonist of the serotonin 5-HT2C receptor, at pharmacologically relevant concentrations, via competitive inhibition. [9] 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.

Inhibition of the 5-HT2C receptor is a suggested factor in the mechanism of anti-depressant effects of agomelatine and maprotiline. The potential selectivity and favorable side effect profile of desmetramadol compared to its prodrug, tramadol, makes it more suitable for clinical use, although no such large scale controlled trials have been conducted with patients.

Upon inhibition of the receptor, downstream signaling causes dopamine and norepinephrine release, and the receptor is thought to significantly regulate mood, anxiety, feeding, and reproductive behavior. 5-HT2C receptors regulate dopamine release in the striatum, prefrontal cortex, nucleus accumbens, hippocampus, hypothalamus, and amygdala, among others.[10]

Research indicates that some suicide victims have an abnormally high number of 5-HT2C receptors in the prefrontal cortex.[11] There is some mixed evidence that agomelatine, a 5-HT2C antagonist, is an effective antidepressant.[12] Antagonism of 5-HT2C receptors by agomelatine results in an increase of dopamine and norepinephrine activity in the frontal cortex.

Pharmacokinetics[edit]

Metabolites[edit]

Desmetramadol is metabolized in the liver into the active metabolite N,O-didesmethyltramadol via CYP3A4 and CYP2B6. The inactive tramadol metabolite N-desmethyltramadol is metabolized into the active metabolite N,O-didesmethyltramadol by CYP2D6.

History[edit]

Society and culture[edit]

Recreational use[edit]

Desmetramadol has recently been marketed as a currently legal substitute for illegal opioid drugs, either in powder form or mixed into various other preparations. One such blend sold under the brand Krypton and containing powdered kratom leaf (Mitragyna speciosa) laced with desmetramadol was reportedly linked to at least 9 accidental deaths from overdose during 2010–2011.[13][14][15]

Medicinal use[edit]

Unusually for a compound that first came to prominance as a recreational designer drug, desmetramadol has recently been reevaluated as a potential novel analgesic 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 clinical trials have shown it to offer similar analgesic benefits to drugs such as oxycodone and fentanyl but with reduced respiratory depression and a comparatively favorable safety profile.[16][4]

Legality[edit]

United Kingdom[edit]

Desmetramadol was made a Class A drug in the United Kingdom on 26 Feb 2013.[17]

USA[edit]

No known legal conflicts, considered legal for research use[citation needed]

See also[edit]

References[edit]

  1. ^ Tramadol Pharmacokinetics, PharmGKB
  2. ^ Sevcik J, Nieber K, Driessen B, Illes P (September 1993). "Effects of the central analgesic tramadol and its main metabolite, O-desmethyltramadol, on rat locus coeruleus neurones". British Journal of Pharmacology. 110 (1): 169–76. doi:10.1111/j.1476-5381.1993.tb13788.x. PMC 2175982. PMID 8220877.
  3. ^ Borlak J, Hermann R, Erb K, Thum T (November 2003). "A rapid and simple CYP2D6 genotyping assay--case study with the analgetic tramadol". Metabolism. 52 (11): 1439–43. doi:10.1016/s0026-0495(03)00256-7. PMID 14624403.
  4. ^ a b Zebala JA, Schuler AD, Kahn SJ, Maeda DY (2019). "Desmetramadol Is Identified as a G-Protein Biased µ Opioid Receptor Agonist". Frontiers in Pharmacology. 10: 1680. doi:10.3389/fphar.2019.01680. PMC 7025522. PMID 32116679.
  5. ^ Potschka H, Friderichs E, Löscher W (September 2000). "Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy". British Journal of Pharmacology. 131 (2): 203–12. doi:10.1038/sj.bjp.0703562. PMC 1572317. PMID 10991912.
  6. ^ Garrido MJ, Valle M, Campanero MA, Calvo R, Trocóniz IF (October 2000). "Modeling of the in vivo antinociceptive interaction between an opioid agonist, (+)-O-desmethyltramadol, and a monoamine reuptake inhibitor, (-)-O-desmethyltramadol, in rats". The Journal of Pharmacology and Experimental Therapeutics. 295 (1): 352–9. PMID 10992001.
  7. ^ Bamigbade TA, Davidson C, Langford RM, Stamford JA (September 1997). "Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus". British Journal of Anaesthesia. 79 (3): 352–6. doi:10.1093/bja/79.3.352. PMID 9389855.
  8. ^ Driessen B, Reimann W, Giertz H (March 1993). "Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro". British Journal of Pharmacology. 108 (3): 806–11. doi:10.1111/j.1476-5381.1993.tb12882.x. PMC 1908052. PMID 8467366.
  9. ^ Horishita T, Minami K, Uezono Y, Shiraishi M, Ogata J, Okamoto T, Shigematsu A (2006). "The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus Oocytes". Pharmacology. 77 (2): 93–9. doi:10.1159/000093179. PMID 16679816. S2CID 23775035.
  10. ^ Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH (July 2007). "Serotonin 5-HT(2C) receptors regulate anxiety-like behavior". Genes, Brain, and Behavior. 6 (5): 491–6. doi:10.1111/j.1601-183X.2007.00316.x. PMID 17451451. S2CID 143950479.
  11. ^ Niswender CM, Herrick-Davis K, Dilley GE, Meltzer HY, Overholser JC, Stockmeier CA, et al. (May 2001). "RNA editing of the human serotonin 5-HT2C receptor. alterations in suicide and implications for serotonergic pharmacotherapy". Neuropsychopharmacology. 24 (5): 478–91. doi:10.1016/S0893-133X(00)00223-2. PMID 11282248.
  12. ^ Eser D, Baghai TC, Möller HJ (June 2010). "Agomelatine: The evidence for its place in the treatment of depression". Core Evidence. 4: 171–9. doi:10.2147/CE.S6005. PMC 2899775. PMID 20694073.
  13. ^ Arndt T, Claussen U, Güssregen B, Schröfel S, Stürzer B, Werle A, Wolf G (May 2011). "Kratom alkaloids and O-desmethyltramadol in urine of a "Krypton" herbal mixture consumer". Forensic Science International. 208 (1–3): 47–52. doi:10.1016/j.forsciint.2010.10.025. PMID 21112167.
  14. ^ Bäckstrom BG, Classon G, Löwenhielm P, Thelander G (2010). "[Krypton--new, deadly Internet drug. Since October 2009 have nine young persons died in Sweden]". Lakartidningen. 107 (50): 3196–7. PMID 21294331.
  15. ^ Kronstrand R, Roman M, Thelander G, Eriksson A (May 2011). "Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton". Journal of Analytical Toxicology. 35 (4): 242–7. doi:10.1093/anatox/35.4.242. PMID 21513619.
  16. ^ Zebala JA, Searle SL, Webster LR, Johnson MS, Schuler AD, Maeda DY, Kahn SJ (October 2019). "Desmetramadol Has the Safety and Analgesic Profile of Tramadol Without Its Metabolic Liabilities: Consecutive Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Trials". The Journal of Pain. 20 (10): 1218–1235. doi:10.1016/j.jpain.2019.04.005. PMC 6790288. PMID 31005596.
  17. ^ "The Misuse of Drugs (Designation) (Amendment) (England, Wales and Scotland) Order 2013". UK Home Office. 31 January 2013.