Editing Dextrorphan

{{Short description|Psychoactive cough suppressant medication}}
{{Distinguish|Dextromethorphan|Dextrallorphan}}
{{Infobox drug
| Verifiedfields     = changed
| Watchedfields      = changed
| verifiedrevid      = 408496712
| IUPAC_name         = (+)-17-methyl-9a,13a,14a-morphinan-3-ol
| image              = Dextrorphan.svg
| image_class        = skin-invert-image
| image2             = Dextrorphane 3d.gif

<!--Clinical data-->| tradename          = 
| legal_US           = Unscheduled<ref>{{Cite web |last=Bensinger |first=Peter |date=October 1, 1976 |title=Dextrophan and Nalbuphine; Removal from Schedules |url=https://www.govinfo.gov/content/pkg/FR-1976-10-01/pdf/FR-1976-10-01.pdf |access-date=June 26, 2023 |website=[[NARA]]}}</ref>

<!--Identifiers-->| CAS_number_Ref     = {{cascite|correct|??}}
| CAS_number         = 125-73-5
| ATC_prefix         = None
| PubChem            = 5360697
| UNII_Ref           = {{fdacite|changed|FDA}}
| UNII               = 04B7QNO9WS
| ChEMBL_Ref         = {{ebicite|changed|EBI}}
| ChEMBL             = 1254766
| ChemSpiderID_Ref   = {{chemspidercite|changed|chemspider}}
| ChemSpiderID       = 10489895
| synonyms           = DXO, Dextrorphanol

<!--Chemical data-->| C                  = 17
| H                  = 23
| N                  = 1
| O                  = 1
| SMILES             = CN1CC[C@@]23CCCC[C@@H]2[C@@H]1Cc4c3cc(O)cc4
| StdInChI_Ref       = {{stdinchicite|changed|chemspider}}
| StdInChI           = 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
| StdInChIKey_Ref    = {{stdinchicite|changed|chemspider}}
| StdInChIKey        = JAQUASYNZVUNQP-PVAVHDDUSA-N
}}

'''Dextrorphan''' ('''DXO''') is a [[psychoactive drug]] of the [[morphinan]] class which acts as an [[antitussive]] or [[cough suppressant]] and in high doses a [[dissociative drug|dissociative]] [[hallucinogen]]. It is the [[dextrorotatory]] [[enantiomer]] of [[racemorphan]]; the [[Levorotation|levorotatory]] enantiomer is [[levorphanol]]. Dextrorphan is produced by O-demethylation of [[dextromethorphan]] by [[CYP2D6]]. Dextrorphan is an [[NMDA receptor antagonist|NMDA antagonist]] and contributes to the psychoactive effects of dextromethorphan.<ref>{{cite journal | vauthors = Zawertailo LA, Kaplan HL, Busto UE, Tyndale RF, Sellers EM | title = Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism: a pilot study | journal = Journal of Clinical Psychopharmacology | volume = 18 | issue = 4 | pages = 332–337 | date = August 1998 | pmid = 9690700 | doi = 10.1097/00004714-199808000-00014 }}</ref>

==Pharmacology==

===Pharmacodynamics===
{| class="wikitable floatleft" style="font-size:small;"
|+ Dextrorphan<ref name="PDSP">{{cite web | title = PDSP K<sub>i</sub> Database | work = Psychoactive Drug Screening Program (PDSP)|author1-link=Bryan Roth| vauthors = Roth BL, Driscol J | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 14 August 2017 | url = https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=dextrorphan&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}</ref><ref name="pmid26826604">{{cite journal | vauthors = Nguyen L, Thomas KL, Lucke-Wold BP, Cavendish JZ, Crowe MS, Matsumoto RR | title = Dextromethorphan: An update on its utility for neurological and neuropsychiatric disorders | journal = Pharmacol. Ther. | volume = 159 | pages = 1–22 | year = 2016 | pmid = 26826604 | doi = 10.1016/j.pharmthera.2016.01.016 }}</ref><ref name="pmid17689532">{{cite journal | vauthors = Werling LL, Keller A, Frank JG, Nuwayhid SJ | title = A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder | journal = Exp. Neurol. | volume = 207 | issue = 2 | pages = 248–57 | year = 2007 | pmid = 17689532 | doi = 10.1016/j.expneurol.2007.06.013 | s2cid = 38476281 }}</ref><ref name="pmid27139517">{{cite journal | vauthors = Taylor CP, Traynelis SF, Siffert J, Pope LE, Matsumoto RR | title = Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use | journal = Pharmacol. Ther. | volume = 164 | pages = 170–82 | year = 2016 | pmid = 27139517 | doi = 10.1016/j.pharmthera.2016.04.010 | doi-access = free }}</ref>
|-
! Site !! K<sub>i</sub> (nM) !! Species !! Ref
|-
| [[NMDA receptor|{{abbr|NMDAR|N-Methyl-D-aspartate receptor}}<br />(MK-801)]] || 486–906 || Rat || <ref name="pmid26826604" />
|-
| [[Sigma-1 receptor|σ<sub>1</sub>]] || 118–481 || Rat || <ref name="pmid26826604" />
|-
| [[Sigma-2 receptor|σ<sub>2</sub>]] || 11,325–15,582 || Rat || <ref name="pmid26826604" />
|-
| {{abbrlink|MOR|μ-Opioid receptor}} || 420<br />&gt;1,000 || Rat<br />Human || <ref name="pmid26826604" /><ref name="pmid7815359">{{cite journal | vauthors = Raynor K, Kong H, Mestek A, Bye LS, Tian M, Liu J, Yu L, Reisine T | title = Characterization of the cloned human mu opioid receptor | journal = J. Pharmacol. Exp. Ther. | volume = 272 | issue = 1 | pages = 423–8 | year = 1995 | pmid = 7815359 }}</ref>
|-
| {{abbrlink|DOR|δ-Opioid receptor}} || 34,700 || Rat || <ref name="pmid26826604" />
|-
| {{abbrlink|KOR|κ-Opioid receptor}} || 5,950 || Rat || <ref name="pmid26826604" />
|-
| {{abbrlink|SERT|Serotonin transporter}} || 401–484 || Rat || <ref name="pmid26826604" />
|-
| {{abbrlink|NET|Norepinephrine transporter}} || ≥340 || Rat || <ref name="pmid26826604" />
|-
| {{abbrlink|DAT|Dopamine transporter}} || >1,000 || Rat || <ref name="pmid26826604" />
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || >1,000 || Rat || <ref name="pmid26826604" />
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]]<sub>/</sub>[[5-HT1D receptor|<sub>1D</sub>]] || 54% at 1&nbsp;μM || Rat || <ref name="pmid26826604" />
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || >1,000 || Rat || <ref name="pmid26826604" />
|-
| [[Alpha-1 adrenergic receptor|α<sub>1</sub>]] ||>1,000 || Rat || <ref name="pmid26826604" />
|-
| [[Alpha-2 adrenergic receptor|α<sub>2</sub>]] || >1,000 || Rat || <ref name="pmid26826604" />
|-
| [[Beta-adrenergic receptor|β]] || 35% at 1&nbsp;μM || Rat || <ref name="pmid26826604" />
|-
| [[D2 receptor|D<sub>2</sub>]] || >1,000 || Rat || <ref name="pmid26826604" />
|-
| [[H1 receptor|H<sub>1</sub>]] || 95% at 1&nbsp;μM || Rat || <ref name="pmid26826604" />
|-
| {{abbrlink|mAChRs|Muscarinic acetylcholine receptors}} || 100% at 1&nbsp;μM || Rat || <ref name="pmid26826604" />
|-
| {{abbrlink|nAChRs|Nicotinic acetylcholine receptors}} || 1,300–29,600<br />(IC<sub>50</sub>) || Rat || <ref name="pmid26826604" />
|-
| {{abbrlink|VDSCs|Voltage-dependent sodium channels}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|- class="sortbottom"
| colspan="4" style="width: 1px;" | Values are K<sub>i</sub> (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 and much less active as a [[serotonin reuptake inhibitor]], but retains DXM's activity as a [[norepinephrine reuptake inhibitor]].<ref>{{cite journal | vauthors = Pechnick RN, Poland RE | title = Comparison of the effects of dextromethorphan, dextrorphan, and levorphanol on the hypothalamo-pituitary-adrenal axis | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 309 | issue = 2 | pages = 515–522 | date = May 2004 | pmid = 14742749 | doi = 10.1124/jpet.103.060038 | s2cid = 274504 }}</ref>
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|date=November 2016}} It is further converted to [[3-Hydroxymorphinan|3-HM]] by [[CYP3A4]] or [[glucuronidation|glucuronidated]].<ref name="DXMdualprobe">{{cite journal | vauthors = Yu A, Haining RL | title = 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? | journal = Drug Metabolism and Disposition | volume = 29 | issue = 11 | pages = 1514–20 | date = November 2001 | pmid = 11602530 | url = http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11602530 }}</ref>

==Society and culture==

===Legal status===
Dextrorphan was formerly a [[Controlled Substances Act#Schedule I controlled substances|Schedule I]] [[controlled substance]] in the [[United States]], but was unscheduled on October 1, 1976.<ref name="urlDextrorphan Legality">{{cite web | url = http://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf | title = Lists of: Scheduling Actions Controlled Substances Regulated Chemicals | author = DEA | access-date = 2010-09-24 | archive-date = 2016-04-17 | archive-url = https://web.archive.org/web/20160417085648/http://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf | url-status = dead }}</ref>

==Research==
Dextrorphan was under development for the treatment of [[stroke]], and reached [[Phases of clinical research#Phase II|phase II]] [[clinical trial]]s for this indication, but development was discontinued.<ref name="AdisInsight">{{Cite web|url=http://adisinsight.springer.com/drugs/800009336|title = Dextrorphan - AdisInsight}}</ref>

==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]].<ref name=Black2021>{{cite journal | vauthors = Black GP, He G, Denison MS, Young TM | title = Using Estrogenic Activity and Nontargeted Chemical Analysis to Identify Contaminants in Sewage Sludge | journal = Environmental Science & Technology | volume = 55 | issue = 10 | pages = 6729–6739 | date = May 2021 | pmid = 33909413 | pmc = 8378343 | doi = 10.1021/acs.est.0c07846 | bibcode = 2021EnST...55.6729B }}</ref>

{{Clear}}

== See also ==
* [[Cough syrup]]
* [[Racemorphan]]; [[Levorphanol]]
* [[Noscapine]]
* [[Codeine]]; [[Pholcodine]]
* [[Dextromethorphan]]; [[Dimemorfan]]
* [[Butamirate]]
* [[Pentoxyverine]]
* [[Tipepidine]]
* [[Cloperastine]]
* [[Levocloperastine]]

==References==
{{Reflist|2}}

{{Antitussives}}
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| list1 = 
{{Drug use}}
{{Hallucinogens}}
}}
{{Navboxes
| title = [[Pharmacodynamics]]
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{{Ionotropic glutamate receptor modulators}}
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[[Category:Antitussives]]
[[Category:Dissociative drugs]]
[[Category:Enantiopure drugs]]
[[Category:Euphoriants]]
[[Category:Morphinans]]
[[Category:Mu-opioid receptor agonists]]
[[Category:Nicotinic antagonists]]
[[Category:NMDA receptor antagonists]]
[[Category:Hydroxyarenes]]
[[Category:Serotonin–norepinephrine reuptake inhibitors]]
[[Category:Sigma agonists]]
[[Category:Human drug metabolites]]