Dextrorphan

Dextrorphan
Clinical data
Other names	DXO, Dextrorphanol
ATC code	None;
Legal status
Legal status	US: Unscheduled;
Identifiers
	IUPAC name (+)-17-methyl-9a,13a,14a-morphinan-3-ol;
CAS Number	125-73-5 ;
PubChem CID	5360697;
ChemSpider	10489895 ;
UNII	04B7QNO9WS;
ChEMBL	ChEMBL1254766 ;
CompTox Dashboard (EPA)	DTXSID301014178 ;
ECHA InfoCard	100.004.323
Chemical and physical data
Formula	C17H23NO
Molar mass	257.377 g·mol−1
3D model (JSmol)	Interactive image;
	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 ; Key:JAQUASYNZVUNQP-PVAVHDDUSA-N ;
	(what is this?) (verify)

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]

Pharmacology

Pharmacodynamics

Dextrorphan^[3]^[4]^[5]^[6]
Site	K_i (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-HT_1A	>1,000	Rat	^[4]
5-HT_1B_/_1D	54% at 1 μM	Rat	^[4]
5-HT_2A	>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 K_i (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.^[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]

Society and culture

Legal status

Dextrorphan was formerly a Schedule I controlled substance in the United States, but was unscheduled on October 1, 1976.^[10]

Research

Dextrorphan was under development for the treatment of stroke, and reached phase II clinical trials for this indication, but development was discontinued.^[11]

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.^[12]

References

^ 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 K_i 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.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t 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.
^ 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. doi:10.1016/S0022-3565(25)24351-8. PMID 7815359.
^ Pechnick RN, Poland RE (May 2004). "Comparison of the effects of dextromethorphan, dextrorphan, and levorphanol on the hypothalamo-pituitary-adrenal axis". The Journal of Pharmacology and Experimental Therapeutics. 309 (2): 515–522. doi:10.1124/jpet.103.060038. PMID 14742749. S2CID 274504.
^ 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.
^ "Dextrorphan - AdisInsight".
^ 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.

[1] Bensinger, Peter (October 1, 1976). "Dextrophan and Nalbuphine; Removal from Schedules" (PDF). NARA. Retrieved June 26, 2023.

[2] 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.

[PDSP-3] Roth BL, Driscol J. "PDSP K_i 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.

[pmid26826604-4] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t 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.

[pmid17689532-5] 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.

[pmid27139517-6] 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.

[pmid7815359-7] 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. doi:10.1016/S0022-3565(25)24351-8. PMID 7815359.

[8] Pechnick RN, Poland RE (May 2004). "Comparison of the effects of dextromethorphan, dextrorphan, and levorphanol on the hypothalamo-pituitary-adrenal axis". The Journal of Pharmacology and Experimental Therapeutics. 309 (2): 515–522. doi:10.1124/jpet.103.060038. PMID 14742749. S2CID 274504.

[DXMdualprobe-9] 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.

[urlDextrorphan_Legality-10] DEA. "Lists of: Scheduling Actions Controlled Substances Regulated Chemicals" (PDF). Archived from the original (PDF) on 2016-04-17. Retrieved 2010-09-24.

[AdisInsight-11] "Dextrorphan - AdisInsight".

[Black2021-12] 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.

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