Dextrorphan

Dextrorphan (DXO) is a psychoactive drug of the morphinan class which acts as an antitussive or cough suppressant and dissociative hallucinogen. It is the dextrorotatory enantiomer of racemorphan; the levorotatory enantiomer is levorphanol. Dextrorphan is produced by O-demethylation of dextromethorphan by CYP2D6. Dextrorphan is an NMDA antagonist and contributes to the psychoactive effects of dextromethorphan.[1]

Not to be confused with Dextromethorphan or Dextrallorphan.
Dextrorphan
Clinical data
Other namesDXO
ATC code
  • None
Legal status
Legal status
  • US: Unscheduled
Identifiers
IUPAC name
  • (+)-17-methyl-9a,13a,14a-morphinan-3-ol
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.004.323
Chemical and physical data
FormulaC17H23NO
Molar mass257.377 g·mol−1
3D model (JSmol)
SMILES
  • CN1CC[C@@]23CCCC[C@@H]2[C@@H]1Cc4c3cc(O)cc4
InChI
  • InChI=1S/C17H23NO/c1-18-9-8-17-7-3-2-4-14(17)16(18)10-12-5-6-13(19)11-15(12)17/h5-6,11,14,16,19H,2-4,7-10H2,1H3/t14-,16+,17+/m1/s1 N
  • Key:JAQUASYNZVUNQP-PVAVHDDUSA-N N
 NY (what is this?)  (verify)

Pharmacology

Pharmacodynamics
Dextrorphan[2][3][4][5]
SiteKi (nM)SpeciesRef
NMDAR
(MK-801)		486–906Rat[3]
σ1118–481Rat[3]
σ211,325–15,582Rat[3]
MOR420
>1,000		Rat
Human		[3][6]
DOR34,700Rat[3]
KOR5,950Rat[3]
SERT401–484Rat[3]
NET≥340Rat[3]
DAT>1,000Rat[3]
5-HT1A>1,000Rat[3]
5-HT1B/1D54% at 1 μMRat[3]
5-HT2A>1,000Rat[3]
α1>1,000Rat[3]
α2>1,000Rat[3]
β35% at 1 μMRat[3]
D2>1,000Rat[3]
H195% at 1 μMRat[3]
mAChRs100% at 1 μMRat[3]
nAChRs1,300–29,600
(IC50)		Rat[3]
VDSCsNDNDND
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

The pharmacology of dextrorphan is similar to that of dextromethorphan (DXM). However, dextrorphan is much more potent as an NMDA receptor antagonist as well much less active as a serotonin reuptake inhibitor, but retains DXM's activity as a norepinephrine reuptake inhibitor.[7]

Pharmacokinetics

Dextrorphan has a notably longer elimination half-life than its parent compound, and therefore has a tendency to accumulate in the blood after repeated administration of normally dosed dextromethorphan formulations. It is further converted to 3-HM or glucuronidated.[8]

Society and culture

Dextrorphan was formerly a Schedule I controlled substance in the United States, but was unscheduled on October 1, 1976.[9]

Research

Dextrorphan was under development for the treatment of stroke, and reached phase II clinical trials for this indication, but development was discontinued.[10]

Environmental presence

In 2021, dextrorphan was identified in >75% of sludge samples taken from 12 wastewater treatment plants in California. The same study associated dextrorphan with estrogenic activity by using predictive modelling, before observing it in in vitro. [11]

See also

References
  1. Zawertailo, L. A.; Kaplan, H. L.; Busto, U. E.; Tyndale, R. F.; Sellers, E. M. (Aug 1998). "Psychotropic Effects of Dextromethorphan are Altered by the CYP2D6 Polymorphism: A Pilot Study". Journal of Clinical Psychopharmacology. 18 (4): 332–337. doi:10.1097/00004714-199808000-00014. PMID 9690700.
  2. Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  3. Nguyen L, Thomas KL, Lucke-Wold BP, Cavendish JZ, Crowe MS, Matsumoto RR (2016). "Dextromethorphan: An update on its utility for neurological and neuropsychiatric disorders". Pharmacol. Ther. 159: 1–22. doi:10.1016/j.pharmthera.2016.01.016. PMID 26826604.
  4. Werling LL, Keller A, Frank JG, Nuwayhid SJ (2007). "A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder". Exp. Neurol. 207 (2): 248–57. doi:10.1016/j.expneurol.2007.06.013. PMID 17689532. S2CID 38476281.
  5. Taylor CP, Traynelis SF, Siffert J, Pope LE, Matsumoto RR (2016). "Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use". Pharmacol. Ther. 164: 170–82. doi:10.1016/j.pharmthera.2016.04.010. PMID 27139517.
  6. Raynor K, Kong H, Mestek A, Bye LS, Tian M, Liu J, Yu L, Reisine T (1995). "Characterization of the cloned human mu opioid receptor". J. Pharmacol. Exp. Ther. 272 (1): 423–8. PMID 7815359.
  7. Pechnick, R. N.; Poland, R. E. (2004). "Comparison of the Effects of Dextromethorphan, Dextrorphan, and Levorphanol on the Hypothalamo-Pituitary-Adrenal Axis". Journal of Pharmacology and Experimental Therapeutics. 309 (2): 515–522. doi:10.1124/jpet.103.060038. PMID 14742749. S2CID 274504.
  8. Yu A, Haining RL (November 2001). "Comparative contribution to dextromethorphan metabolism by cytochrome P450 isoforms in vitro: can dextromethorphan be used as a dual probe for both CTP2D6 and CYP3A activities?". Drug Metabolism and Disposition. 29 (11): 1514–20. PMID 11602530.
  9. DEA. "Lists of: Scheduling Actions Controlled Substances Regulated Chemicals" (PDF). Retrieved 2010-09-24.
  10. "Dextrorphan - AdisInsight".
  11. Gabrielle P. Black (2021). "Using Estrogenic Activity and Nontargeted Chemical Analysis to Identify Contaminants in Sewage Sludge". Environmental Science & Technology. 55 (10): 6729–6739. Bibcode:2021EnST...55.6729B. doi:10.1021/acs.est.0c07846. PMC 8378343. PMID 33909413.
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