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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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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]
Site | Ki (nM) | Species | Ref |
---|---|---|---|
NMDAR (MK-801) | 486–906 | Rat | [4] |
σ1 | 118–481 | Rat | [4] |
σ2 | 11,325–15,582 | Rat | [4] |
MOR Tooltip μ-Opioid receptor | 420 >1,000 | Rat Human | [4] [7] |
DOR Tooltip δ-Opioid receptor | 34,700 | Rat | [4] |
KOR Tooltip κ-Opioid receptor | 5,950 | Rat | [4] |
SERT Tooltip Serotonin transporter | 401–484 | Rat | [4] |
NET Tooltip Norepinephrine transporter | ≥340 | Rat | [4] |
DAT Tooltip 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] |
mAChRs Tooltip Muscarinic acetylcholine receptors | 100% at 1 μM | Rat | [4] |
nAChRs Tooltip Nicotinic acetylcholine receptors | 1,300–29,600 (IC50) | Rat | [4] |
VDSCs Tooltip 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.
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]
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]
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.
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).
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.
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.
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).
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.
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.
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.
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.
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.
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.
Racemorphan, or morphanol, is the racemic mixture of the two stereoisomers of 17-methylmorphinan-3-ol, each with differing pharmacology and effects:
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.
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.
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.
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.
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.