Dextrallorphan

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Dextrallorphan
Dextrallorphan.svg
Systematic (IUPAC) name
(+)-(13α,14α)-17-allylmorphinan-3-ol
Clinical data
Legal status
  • Uncontrolled
Routes Oral
Identifiers
CAS number 5822-43-5
ATC code None
PubChem CID 5748237
ChemSpider 2339009
Chemical data
Formula C19H25NO 
Mol. mass 283.41 g/mol

Dextrallorphan (DXA) is an opioid derivative drug of the morphinan class and is used in scientific research. It acts as a σ1 receptor agonist and NMDA receptor antagonist.[1][2][3][4] It has no significant affinity for the σ2, μ-opioid, or δ-opioid receptor, or for the serotonin or norepinephrine transporter.[5][2] As an NMDA receptor antagonist, in vivo, it is approximately twice as potent as dextromethorphan, and five-fold less potent than dextrorphan.[3]

Regulatory Status[edit]

Dextrallorphan is specifically used for scientific research and has not been approved for use as a pharmaceutical by the FDA and therefore has no therapeutic equivalence evaluations. [6] However, dextromethorphan (DXM), a drug compound in the same morphinan class as dextrallorphan, is FDA approved for use in cough medicine. These medicines are currently sold over-the counter, but due to the recent increase in teen abuse of cough medicine, preventative actions are being taken in some states to prohibit the sale of cough medicine to minors. [7]

Market Comparison[edit]

While dextrallorphan is not FDA approved for use due to its lack of significant pharmacological effects, some of its similar drugs compounds are. One of these includes its closely related compound dextromethorphan (DXM), which was FDA approved in 1958 and is found in over 100 over-the-counter cough medicines. [7][8] Additionally, dextrorphan (DXO), a drug compound similar to both dextrallorphan and dextromethorphan, is also FDA approved and on the market as a cough suppressant and is sold for scientific research. [9] [10]

Uses in Scientific Research[edit]

Masking of sigma-1 receptor[edit]

Dextrallorphan is often used in research to block σ1 receptor sites so that σ2 receptor sites (which have not been cloned yet) can be studied. [11] [12] [13] It was hypothesized that both of these sigma (σ) receptors were opioid receptors, due to their affinity for psychoactive drugs. However, it is now understood that they are non-opioid receptors that bind to certain psychoactive drugs, like dextrallorphan. [14] One example of dextrallorphan being used to mask σ1 receptor sites was seen in a study on the localization of the σ2 receptor in detergent-resistant lipid raft domains.[11] It has also been used to mask σ1 receptor sites so that σ2 receptor binding characteristics in the rat liver could be determined, by labeling σ2 receptor sites with [3H]l,3-di-o-tolylguanidine (DTG) in the presence of 1 μM dextrallorphan solution. [13]

Animal Studies[edit]

Dextrallorphan was used in Spraque-Dawley rats to study cerebellar Purkinje neurons electrophysical responses to the drug when it was applied iontophoretically as a sigma (σ) receptor ligand. Dextrallorphan increased the firing rate by 14%, suggesting that sigma (σ) ligands (like dextrallorphan) alter the spontaneous firing of Purkinje neurons and cause motor effects. [15]

In another study, dextrallorphan, along with other opioid derivatives, was found to be a potent inhibitor of etorphine-inaccessible (EI) sites in the guinea-pig brain. Dextrallorphan was of the top three most potent opioid inhibitors of those studied, with a concentration of 67 nM required to show 50% inhibition. [1]

History[edit]

In 1955, dextrallorphan has been used to study inhibition of cholinesterase's and to look at the relationship between analgetics and acetylcholine metabolism. [16] It was found that dextrallorphan inhibits 25% of bovine erythrocyte cholinesterase at a dose of 10-3 mole/liter, which corresponds to a concentration of up to 0.2 mg/kg in dog intestine. However, at this dose the drug showed no effect on the gut tone. Dextrallorphan was classified as a potent inhibitor of the intestinal and red blood cell cholinesterase based on the concentration of the drug needed to inhibit these enzymes in the cholinesterase preparations from the animals systems utilized. Simultaneously, dextrallorphan showed no analgesia and no change in intestinal tone. With these results dextrallorphan helped proved that there is no correlation between the inhibition of cholinesterase systems and analgetic or intestinal effects. [17]

In 1979, dextrallorphan was found to have a half maximal inhibitory concentration (IC50) for binding to the pituitary and brain receptor of 10,000 ± 1000 nM and 10,000 ± 1500 nM, respectively. While its stereoisomer, levellorphan, had a 10,000 times more potent dose, thus proving that binding to these receptors is stereospecific.[18]

See also[edit]

References[edit]

  1. ^ a b Su, T. P. (Nov 1982). "Evidence for Sigma Opioid Receptor: Binding of [3H]SKF-10047 to Etorphine-Inaccessible Sites in Guinea-Pig Brain" (pdf). The Journal of Pharmacology and Experimental Therapeutics 223 (2): 284–290. PMID 6290634. 
  2. ^ a b Codd, E. E.; Shank, R. P.; Schupsky, J. J.; Raffa, R. B. (Sep 1995). "Serotonin and Norepinephrine Uptake Inhibiting Activity of Centrally Acting Analgesics: Structural Determinants and Role in Antinociception" (pdf). The Journal of Pharmacology and Experimental Therapeutics 274 (3): 1263–1270. PMID 7562497. 
  3. ^ a b Shukla, V. K.; Lemaire, S. (Jan 1997). "N-Methyl-D-Aspartate Antagonist Activity of Alpha- and Beta-Sulfallorphans" (pdf). The Journal of Pharmacology and Experimental Therapeutics 280 (1): 357–365. PMID 8996216. 
  4. ^ Shannon, H. E. (Apr 1983). "Pharmacological Evaluation of N-Allynormetazocine (SKF 10,047) on the Basis of its Discriminative Stimulus Properties in the Rat". The Journal of Pharmacology and Experimental Therapeutics 225 (1): 144–152. PMID 6834266. 
  5. ^ He, X. S.; Bowen, W. D.; Lee, K. S.; Williams, W.; Weinberger, D. R.; de Costa, B. R. (Mar 1993). "Synthesis and Binding Characteristics of Potential SPECT Imaging Agents for Sigma-1 and Sigma-2 Binding Sites". Journal of Medicinal Chemistry 36 (5): 566–571. doi:10.1021/jm00057a006. PMID 8496936. 
  6. ^ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". fda.gov. U.S. Food and Drug Administration. Retrieved 10 December 2014. 
  7. ^ a b "Dextromethorphan (DXM)". Center for Substance Abuse Research. Retrieved 10 December 2014. 
  8. ^ "Dextromethorphan: Preventing Teen Cough Medicine Abuse". Customer Healthcare Products Association. Retrieved 10 December 2014. 
  9. ^ "What is Dextrorphan?". wiseGEEK. Retrieved 10 December 2014. 
  10. ^ "Dextrorphan". Sigma-Aldrich. Retrieved 10 December 2014. 
  11. ^ a b Gebreselassie, D.; Bowen, W. D. (June 2004). "Sigma-2 receptors are specifically localized to lipid rafts in rat liver membranes" (pdf). European Journal of Pharmacology 493 (1-3): 19–28. PMID 15189760. 
  12. ^ Maeda, D. Y.; Williams, W.; Bowen, W. D.; Coop, A. (Jan 2000). "SA sigma-1 receptor selective analogue of BD1008. a potential substitute for (+)-opioids in sigma receptor binding assays" (pdf). Bioorganic & Medicinal Chemistry Letters 10 (1): 17–18. PMID 10636233. 
  13. ^ a b Torrence-Campbell, C.; Bowen, W. D. (May 1996). "Differential solubilization of rat liver sigma-1 and sigma- 2 receptors: retention of sigma- 2 sites in particulate fractions" (pdf). European Journal of Pharmacology 304 (1-3): 201–210. PMID 11988171. 
  14. ^ Hayashi, T.; Su, T. (Oct 2005). "The Sigma Receptor: Evolution of the Concept in Neuropsychopharmacology" (pdf). Current Neuropharmacology 3 (4): 267–280. PMC 2268997. 
  15. ^ Martin, W. J.; De Costa, B. R.; Walker, J. M. (1994). [hhttp://www.sciencedirect.com/science/article/pii/0361923094901066 "Effects of σ ligands on rat cerebellar purkinje neuron firing: An iontophoretic study"] (pdf). Brain Research Bulletin 35 (4): 303–309. 
  16. ^ Eikenburg, D. C.; Stickney, J. L. (1979). "Anti-Cholinesterase Activity of 1-α-acetylmethadol: Relationship of Bradycardia" (pdf). General Pharmacology 10 (3): 195–200. PMID 467958. 
  17. ^ Young, D. C.; Vander Ploeg, A.; Featherstone, R. M.; Gross, E. G. (May 1955). "The Interrelationships Among the Central, Peripheral and Anticholinesterase Effects of Some Morphinan Derivatives" (pdf). The Journal of Pharmacology and Experimental Therapeutics 114 (2): 33–37. PMID 14392568. 
  18. ^ Simantov, R.; Snyder, S. H. (Dec 1976). "Opiate receptor binding in the pituitary gland" (pdf). Brain Research 124 (1): 178–184. PMID 191146.