Dextrorphan
Dextrorphan
Psychoactive cough suppressant medication
Dextrorphan (DXO) is a psychoactive drug of the morphinan class which acts as an antitussive or cough suppressant and in high doses a 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.[2]
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| Other names | DXO, Dextrorphanol |
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| ECHA InfoCard | 100.004.323  |
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| Formula | C17H23NO |
| Molar mass | 257.377 g·mol−1 |
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Pharmacodynamics
| Site | Ki (nM) | Species | Ref |
|---|---|---|---|
| NMDAR (MK-801) | 486–906 | Rat | [4] |
| σ1 | 118–481 | Rat | [4] |
| σ2 | 11,325–15,582 | Rat | [4] |
| MORTooltip μ-Opioid receptor | 420 >1,000 | Rat Human | [4][7] |
| DORTooltip δ-Opioid receptor | 34,700 | Rat | [4] |
| KORTooltip κ-Opioid receptor | 5,950 | Rat | [4] |
| SERTTooltip Serotonin transporter | 401–484 | Rat | [4] |
| NETTooltip Norepinephrine transporter | ≥340 | Rat | [4] |
| DATTooltip Dopamine transporter | >1,000 | Rat | [4] |
| 5-HT1A | >1,000 | Rat | [4] |
| 5-HT1B/1D | 54% at 1 μM | Rat | [4] |
| 5-HT2A | >1,000 | Rat | [4] |
| α1 | >1,000 | Rat | [4] |
| α2 | >1,000 | Rat | [4] |
| β | 35% at 1 μM | Rat | [4] |
| D2 | >1,000 | Rat | [4] |
| H1 | 95% at 1 μM | Rat | [4] |
| mAChRsTooltip Muscarinic acetylcholine receptors | 100% at 1 μM | Rat | [4] |
| nAChRsTooltip Nicotinic acetylcholine receptors | 1,300–29,600 (IC50) | Rat | [4] |
| VDSCsTooltip Voltage-dependent sodium channels | ND | ND | ND |
| 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.[8] It also has more affinity for the opioid receptors than dextromethorphan, significantly so at high doses.
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.[citation needed] It is further converted to 3-HM by CYP3A4 or glucuronidated.[9]
Legal status
Dextrorphan was formerly a Schedule I controlled substance in the United States, but was unscheduled on October 1, 1976.[10]
Dextrorphan was under development for the treatment of stroke, and reached phase II clinical trials for this indication, but development was discontinued.[11]
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. [12]
- Bensinger, Peter (October 1, 1976). "Dextrophan and Nalbuphine; Removal from Schedules" (PDF). NARA. Retrieved June 26, 2023.
- Zawertailo LA, Kaplan HL, Busto UE, Tyndale RF, Sellers EM (August 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- DEA. "Lists of: Scheduling Actions Controlled Substances Regulated Chemicals" (PDF). Archived from the original (PDF) on 2016-04-17. Retrieved 2010-09-24.
- Black GP, He G, Denison MS, Young TM (May 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.