Dextrorphan

Last updated
Dextrorphan
Dextrorphan.svg
Dextrorphane 3d.gif
Clinical data
Other namesDXO, Dextrorphanol
ATC code
  • None
Legal status
Legal status
  • US:Unscheduled [1]
Identifiers
  • (+)-17-methyl-9a,13a,14a-morphinan-3-ol
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.004.323 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H23NO
Molar mass 257.377 g·mol−1
3D model (JSmol)
  • CN1CC[C@@]23CCCC[C@@H]2[C@@H]1Cc4c3cc(O)cc4
  • 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 X mark.svgN
  • Key:JAQUASYNZVUNQP-PVAVHDDUSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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. [2]

Contents

Pharmacology

Pharmacodynamics

Dextrorphan [3] [4] [5] [6]
SiteKi (nM)SpeciesRef
NMDAR
(MK-801)
486–906Rat [4]
σ1 118–481Rat [4]
σ2 11,325–15,582Rat [4]
MOR Tooltip μ-Opioid receptor420
>1,000
Rat
Human
[4] [7]
DOR Tooltip δ-Opioid receptor34,700Rat [4]
KOR Tooltip κ-Opioid receptor5,950Rat [4]
SERT Tooltip Serotonin transporter401–484Rat [4]
NET Tooltip Norepinephrine transporter≥340Rat [4]
DAT Tooltip Dopamine transporter>1,000Rat [4]
5-HT1A >1,000Rat [4]
5-HT1B / 1D 54% at 1 μMRat [4]
5-HT2A >1,000Rat [4]
α1 >1,000Rat [4]
α2 >1,000Rat [4]
β 35% at 1 μMRat [4]
D2 >1,000Rat [4]
H1 95% at 1 μMRat [4]
mAChRs Tooltip Muscarinic acetylcholine receptors100% at 1 μMRat [4]
nAChRs Tooltip Nicotinic acetylcholine receptors1,300–29,600
(IC50)
Rat [4]
VDSCs Tooltip Voltage-dependent sodium channelsNDNDND
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]

Society and culture

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]

See also

Related Research Articles

<span class="mw-page-title-main">Recreational use of dextromethorphan</span> Typical nonmedical means DXM (an OTC cough suppressant drug) is often abused.

Dextromethorphan, or DXM, a common active ingredient found in many over-the-counter cough suppressant cold medicines, is used as a recreational drug and entheogen for its dissociative effects. It has almost no psychoactive effects at medically recommended doses. However, dextromethorphan has powerful dissociative properties when administered in doses well above those considered therapeutic for cough suppression. Recreational use of DXM is sometimes referred to in slang form as "robo-tripping", whose prefix derives from the Robitussin brand name, or "Triple Cs", which derives from the Coricidin brand whose tablets are printed with "CC+C" for "Coricidin Cough and Cold". However, this brand presents additional danger when used at recreational doses due to the presence of chlorpheniramine.

<span class="mw-page-title-main">Tramadol</span> Medication of the opioid type

Tramadol, sold under the brand name Ultram among others, is an opioid pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It is available in combination with paracetamol (acetaminophen).

<span class="mw-page-title-main">Dextromethorphan</span> Antitussive medication of the dissociative class

Dextromethorphan (DXM) is a cough suppressant in over-the-counter cold and cough medicines. It affects NMDA, glutamate-1, and sigma-1 receptors in the brain, all of which have been implicated in the pathophysiology of depression. In 2022, the FDA approved a formulation of it combined with bupropion named Auvelity to serve as a rapid acting antidepressant in patients with major depressive disorder.

Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as 4-PPBP, SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, sigma-1 receptors (σ1) and sigma-2 receptors (σ2), which are classified as sigma receptors for their pharmacological similarities, even though they are evolutionarily unrelated.

<span class="mw-page-title-main">Levorphanol</span> Chemical compound

Levorphanol is an opioid medication used to treat moderate to severe pain. It is the levorotatory enantiomer of the compound racemorphan. Its dextrorotatory counterpart is dextrorphan.

<span class="mw-page-title-main">Morphinan</span> Chemical compound

Morphinan is the prototype chemical structure of a large chemical class of psychoactive drugs, consisting of opiate analgesics, cough suppressants, and dissociative hallucinogens, among others. Typical examples include compounds such as morphine, codeine, and dextromethorphan (DXM). Despite related molecular structures, the pharmacological profiles and mechanisms of action between the various types of morphinan substances can vary substantially. They tend to function either as μ-opioid receptor agonists (opioids), or NMDA receptor antagonists (dissociatives).

<span class="mw-page-title-main">Levomethorphan</span> Opioid analgesic

Levomethorphan (LVM) (INN, BAN) is an opioid analgesic of the morphinan family that has never been marketed. It is the L-stereoisomer of racemethorphan (methorphan). The effects of the two isomers of racemethorphan are quite different, with dextromethorphan (DXM) being an antitussive at low doses and a dissociative hallucinogen at much higher doses. Levomethorphan is about five times stronger than morphine.

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce is referred to as dissociative anesthesia.

<span class="mw-page-title-main">Muscarinic antagonist</span> Drug that binds to but does not activate muscarinic cholinergic receptors

A muscarinic receptor antagonist (MRA) is a type of anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor. The muscarinic receptor is a protein involved in the transmission of signals through certain parts of the nervous system, and muscarinic receptor antagonists work to prevent this transmission from occurring. Notably, muscarinic antagonists reduce the activation of the parasympathetic nervous system. The normal function of the parasympathetic system is often summarised as "rest-and-digest", and includes slowing of the heart, an increased rate of digestion, narrowing of the airways, promotion of urination, and sexual arousal. Muscarinic antagonists counter this parasympathetic "rest-and-digest" response, and also work elsewhere in both the central and peripheral nervous systems.

<span class="mw-page-title-main">Dimemorfan</span> Cough suppressant

Dimemorfan (INN), or dimemorfan phosphate (JAN), also known as 3,17-dimethylmorphinan, is an antitussive of the morphinan family that is widely used in Japan and is also marketed in Spain and Italy. It was developed by Yamanouchi Pharmaceutical and introduced in Japan in 1975. It was later introduced in Spain in 1981 and Japan in 1985.

<span class="mw-page-title-main">Serotonin reuptake inhibitor</span> Class of drug

A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin by blocking the action of the serotonin transporter (SERT). This in turn leads to increased extracellular concentrations of serotonin and, therefore, an increase in serotonergic neurotransmission. It is a type of monoamine reuptake inhibitor (MRI); other types of MRIs include dopamine reuptake inhibitors and norepinephrine reuptake inhibitors.

<span class="mw-page-title-main">Afimoxifene</span> Chemical compound

Afimoxifene, also known as 4-hydroxytamoxifen (4-OHT) and by its tentative brand name TamoGel, is a selective estrogen receptor modulator (SERM) of the triphenylethylene group and an active metabolite of tamoxifen. The drug is under development under the tentative brand name TamoGel as a topical gel for the treatment of hyperplasia of the breast. It has completed a phase II clinical trial for cyclical mastalgia, but further studies are required before afimoxifene can be approved for this indication and marketed.

<span class="mw-page-title-main">Racemorphan</span> Racemic mixture

Racemorphan, or morphanol, is the racemic mixture of the two stereoisomers of 17-methylmorphinan-3-ol, each with differing pharmacology and effects:

<span class="mw-page-title-main">Dextrallorphan</span> Chemical compound

Dextrallorphan (DXA) is a chemical of the morphinan class that is used in scientific research. It acts as a σ1 receptor agonist and NMDA receptor antagonist. It has no significant affinity for the σ2, μ-opioid, or δ-opioid receptor, or for the serotonin or norepinephrine transporter. As an NMDA receptor antagonist, in vivo, it is approximately twice as potent as dextromethorphan, and five-fold less potent than dextrorphan.

<span class="mw-page-title-main">3-Hydroxymorphinan</span> Chemical compound

3-Hydroxymorphinan (3-HM), or morphinan-3-ol, is a psychoactive drug of the morphinan family. It is the racemic counterpart to norlevorphanol.

Dextromethorphan/quinidine, sold under the brand name Nuedexta, is a fixed-dose combination medication for the treatment of pseudobulbar affect (PBA). It contains dextromethorphan (DXM) and the class I antiarrhythmic agent quinidine.

<span class="mw-page-title-main">Dextromethorphan/bupropion</span> Combination medication

Dextromethorphan/bupropion (DXM/BUP), sold under the brand name Auvelity, is a combination medication for the treatment of major depressive disorder (MDD). Its active components are dextromethorphan (DXM) and bupropion. Patients who stayed on the medication had an average of 11% greater reduction in depressive symptoms than placebo in an FDA approval trial. It is taken as a tablet by mouth.

<span class="mw-page-title-main">Triazoledione</span> Phenylpiperazine compound

Triazoledione is a phenylpiperazine compound and a major metabolite of the antidepressant nefazodone. It is active, but with substantially reduced potency compared to nefazodone. As such, it has been suggested that it is unlikely that triazoledione contributes significantly to the pharmacology of nefazodone. However, triazoledione may reach concentrations as great as 10 times those of nefazodone, and hence could still be a significant contributor to its therapeutic effects.

<span class="mw-page-title-main">Amesergide</span> Chemical compound

Amesergide is a serotonin receptor antagonist of the ergoline and lysergamide families related to methysergide which was under development by Eli Lilly and Company for the treatment of a variety of conditions including depression, anxiety, schizophrenia, male sexual dysfunction, migraine, and thrombosis but was never marketed. It reached phase II clinical trials for the treatment of depression, erectile dysfunction, and premature ejaculation prior to the discontinuation of its development.

Deudextromethorphan/quinidine is a combination of deudextromethorphan and quinidine (Q) which is under development by Avanir Pharmaceuticals for the treatment of a variety of neurological and psychiatric indications. The pharmacological profile of d-DXM/Q is similar to that of dextromethorphan/quinidine (DXM/Q). DXM and d-DXM act as σ1 receptor agonists, NMDA receptor antagonists, and serotonin–norepinephrine reuptake inhibitors, among other actions, while quinidine is an antiarrhythmic agent acting as a CYP2D6 inhibitor. Quinidine inhibits the metabolism of DXM and d-DXM into dextrorphan (DXO), which has a different pharmacological profile from DXM. Deuteration of DXM hinders its metabolism by CYP2D6 into DXO, thereby allowing for lower doses of quinidine in the combination. This in turn allows for lower potential for drug interactions and cardiac adverse effects caused by quinidine. As of September 2020, d-DXM/Q is in phase 3 clinical trials for agitation, phase 2/3 trials for schizophrenia, and phase 2 trials for brain injuries, impulse control disorders, major depressive disorder, and neurodegenerative disorders.

References

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  3. 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.
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  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.
  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.
  10. DEA. "Lists of: Scheduling Actions Controlled Substances Regulated Chemicals" (PDF). Archived from the original (PDF) on 2016-04-17. Retrieved 2010-09-24.
  11. "Dextrorphan - AdisInsight".
  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.