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Chemistry

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Also known as: D-methorphan, 125-71-3, Delta-methorphan, Dextromorphan, Dextromethorfan, Destrometerfano
Molecular Formula
C18H25NO
Molecular Weight
271.4  g/mol
InChI Key
MKXZASYAUGDDCJ-NJAFHUGGSA-N
FDA UNII
7355X3ROTS

Dextromethorphan
Methyl analog of DEXTRORPHAN that shows high affinity binding to several regions of the brain, including the medullary cough center. This compound is an NMDA receptor antagonist (RECEPTORS, N-METHYL-D-ASPARTATE) and acts as a non-competitive channel blocker. It is one of the widely used ANTITUSSIVES, and is also used to study the involvement of glutamate receptors in neurotoxicity.
Dextromethorphan is an Uncompetitive N-methyl-D-aspartate Receptor Antagonist and Sigma-1 Agonist. The mechanism of action of dextromethorphan is as an Uncompetitive NMDA Receptor Antagonist and Sigma-1 Receptor Agonist.
1 2D Structure

Dextromethorphan

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
(1S,9S,10S)-4-methoxy-17-methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene
2.1.2 InChI
InChI=1S/C18H25NO/c1-19-10-9-18-8-4-3-5-15(18)17(19)11-13-6-7-14(20-2)12-16(13)18/h6-7,12,15,17H,3-5,8-11H2,1-2H3/t15-,17+,18+/m1/s1
2.1.3 InChI Key
MKXZASYAUGDDCJ-NJAFHUGGSA-N
2.1.4 Canonical SMILES
CN1CCC23CCCCC2C1CC4=C3C=C(C=C4)OC
2.1.5 Isomeric SMILES
CN1CC[C@@]23CCCC[C@@H]2[C@@H]1CC4=C3C=C(C=C4)OC
2.2 Other Identifiers
2.2.1 UNII
7355X3ROTS
2.3 Synonyms
2.3.1 MeSH Synonyms

1. D-methorphan

2. Delsym

3. Dextromethorphan Hydrobromide

4. Dextromethorphan Hydrobromide, (+-)-isomer

5. Dextromethorphan Hydrobromide, Monohydrate

6. Dextromethorphan Hydrochloride

7. Dextromethorphan, (+-)-isomer

8. Hydrobromide, Dextromethorphan

9. Hydrochloride, Dextromethorphan

10. L-methorphan

11. Levomethorphan

12. Racemethorphan

2.3.2 Depositor-Supplied Synonyms

1. D-methorphan

2. 125-71-3

3. Delta-methorphan

4. Dextromorphan

5. Dextromethorfan

6. Destrometerfano

7. Dextrometorfano

8. Albutussin

9. Dextromethorphane

10. Dextromethorphanum

11. Ba 2666

12. (+)-dextromethorphan

13. Benylin Dm

14. Nodex

15. Hsdb 3056

16. Dextromethorfan [czech]

17. Destrometerfano [dcit]

18. Morphinan, 3-methoxy-17-methyl-, (9alpha,13alpha,14alpha)-

19. 3-methoxy-17-methyl-9alpha,13alpha,14alpha-morphinan

20. Dextrometorphan

21. Romilar

22. Dextrometorfano [inn-spanish]

23. (+)-3-methoxy-17-methylmorphinan

24. 7355x3rots

25. Nsc-751452

26. (1s,9s,10s)-4-methoxy-17-methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene

27. Ba-2666

28. Morphinan, 3-methoxy-17-methyl-, (9.alpha.,13.alpha.,14.alpha.)-

29. Balminil Dm

30. 3-methoxy-17-methyl-9.alpha.,13.alpha.,14.alpha.-morphinan

31. Dextromethorphane [inn-french]

32. Dextromethorphanum [inn-latin]

33. Dextromethorphan [usp:inn:ban]

34. Dxm [antitussive]

35. ( )-3-methoxy-n-methylmorphinon

36. Dextromethorphan (usp)

37. Einecs 204-752-2

38. Chebi:4470

39. Brn 0088549

40. Unii-7355x3rots

41. Calmylin

42. (+)-3-methoxy-n-methylmorphinon

43. Delsym (salt/mix)

44. Medicon (salt/mix)

45. Romilar (salt/mix)

46. Tusilan (salt/mix)

47. 9alpha,13alpha,14alpha-morphinan, 3-methoxy-17-methyl-

48. Prestwick0_000359

49. Prestwick1_000359

50. Prestwick2_000359

51. Prestwick3_000359

52. Lopac-d-2531

53. Racemethorphan [as D-form]

54. ( )-cis-1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2h-10,4alpha-iminoethanophenanthren

55. Schembl29949

56. Bspbio_000457

57. Dextromethorphan [mi]

58. 4-21-00-01367 (beilstein Handbook Reference)

59. Chembl52440

60. Dextromethorphan [inn]

61. Spbio_002378

62. Dextromethorphan [hsdb]

63. Bpbio1_000503

64. Gtpl6953

65. Dextromethorphan [vandf]

66. (9alpha,13alpha,14alpha)-3-methoxy-17-methylmorphinan

67. Dextromethorphan [mart.]

68. Dtxsid3022908

69. Chebi:92579

70. (+)-3-methoxy-n-methylmorphinan

71. Dextromethorphan [usp-rs]

72. Dextromethorphan [who-dd]

73. (9alpha,13alpha,14alpha)-17-methyl-3-(methyloxy)morphinan

74. 9-alpha,13-alpha,14-alpha-morphinan, 3-methoxy-17-methyl-

75. Hms2090c08

76. Lsm-2726

77. Morphinan, 3-methoxy-17-methyl-, (9-alpha,13-alpha,14-alpha)-

78. Zinc3201907

79. Bdbm50366613

80. Akos025311415

81. Db00514

82. Nsc 751452

83. (+)-cis-1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2h-10,4alpha-iminoethanophenanthren

84. Dextromethorphan [usp Monograph]

85. Ncgc00015333-01

86. Ncgc00015333-02

87. 3-methoxy-17-methyl-9a,13a,14a-morphinan

88. (9a,13a,14a)-3-methoxy-17-methylmorphinan

89. C06947

90. D03742

91. Q407781

92. 3-methoxy-17-methyl-9.alpha.,13.alpha.-morphinan

93. J-005274

94. Brd-k33211335-337-03-7

95. Morphinan, 3-methoxy-17-methyl-, (9?,13?,14?)-

96. (+)-3-methoxy-17-methyl-9alpha,13alpha,14alpha-morphinan

97. 9.alpha.,13.alpha.,14.alpha.-morphinan, 3-methoxy-17-methyl-

98. 9alpha,13alpha,14alpha-morphinan, 3-methoxy-17-methyl- (8ci)

99. 3-methoxy-17-methylmorphinan-, (9.alpha.,13.alpha.,14.alpha.)- #

100. 4-methoxy-12-methyl-12-azatetracyclo[9.3^1.10^.0^2.7^] Heptadeca-2(7),3,5-triene

101. (1r,9r,10r)-4-methoxy-17-methyl-17-azatetracyclo[7.5.3.0^{1,10}.0^{2,7}]heptadeca-2,4,6-triene

102. (4as,10s,10as)-6-methoxy-11-methyl-1,3,4,9,10,10a-hexahydro-2h-10,4a-(epiminoethano)phenanthrene

103. Dextromethorphan Solution, 1.0 Mg/ml In Methanol, Ampule Of 1 Ml, Certified Reference Material

2.4 Create Date
2005-06-08
3 Chemical and Physical Properties
Molecular Weight 271.4 g/mol
Molecular Formula C18H25NO
XLogP33.4
Hydrogen Bond Donor Count0
Hydrogen Bond Acceptor Count2
Rotatable Bond Count1
Exact Mass271.193614421 g/mol
Monoisotopic Mass271.193614421 g/mol
Topological Polar Surface Area12.5 Ų
Heavy Atom Count20
Formal Charge0
Complexity370
Isotope Atom Count0
Defined Atom Stereocenter Count3
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Information
1 of 2  
Drug NameDelsym
Active IngredientDextromethorphan polistirex
Dosage FormSuspension, extended release
RouteOral
Strengtheq 30mg hbr/5ml
Market StatusOver the Counter
CompanyReckitt Benckiser

2 of 2  
Drug NameDelsym
Active IngredientDextromethorphan polistirex
Dosage FormSuspension, extended release
RouteOral
Strengtheq 30mg hbr/5ml
Market StatusOver the Counter
CompanyReckitt Benckiser

4.2 Therapeutic Uses

Antitussive Agents; Excitatory Amino Acid Antagonists

National Library of Medicine's Medical Subject Headings. Dextromethorphan. Online file (MeSH, 2017). Available from, as of August 30, 2017: https://www.nlm.nih.gov/mesh/2017/mesh_browser/MBrowser.html


/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Dextromethorphan is included in the database.

NIH/NLM; ClinicalTrials.Gov. Available from, as of August 30, 2017: https://clinicaltrials.gov/


Dextromethorphan is used for the temporary relief of coughs caused by minor throat and bronchial irritation such as may occur with common colds or with inhaled irritants. Dextromethorphan is most effective in the treatment of chronic, nonproductive cough. The drug is a common ingredient in commercial cough mixtures available without prescription.

American Society of Health-System Pharmacists 2017; Drug Information 2017. Bethesda, MD. 2017, p. 2931


Dextromethorphan preparations are administered orally. Lozenges containing dextromethorphan hydrobromide should not be used in children younger than 6 years of age and liquid-filled capsules containing the drug should not be used in children younger than 12 years of age, unless otherwise directed by a clinician.

OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 2931


For more Therapeutic Uses (Complete) data for Dextromethorphan (20 total), please visit the HSDB record page.


4.3 Drug Warning

Administration of dextromethorphan may be associated with histamine release, and the drug should be used with caution in atopic children. Dextromethorphan also should be used with caution in sedated or debilitated patients and in patients confined to the supine position. Dextromethorphan should not be taken for persistent or chronic cough (e.g., with smoking, emphysema, asthma) or when coughing is accompanied by excessive secretions, unless directed by a clinician. If cough persists for longer than 1 week, tends to recur, or is accompanied by high fever, rash, or persistent headache, a clinician should be consulted.

American Society of Health-System Pharmacists 2017; Drug Information 2017. Bethesda, MD. 2017, p. 2931


Individuals with phenylketonuria (i.e., homozygous deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that some commercially available preparations of dextromethorphan contain aspartame, which is metabolized in the GI tract to phenylalanine following oral administration.

American Society of Health-System Pharmacists 2017; Drug Information 2017. Bethesda, MD. 2017, p. 2931


Adverse effects with dextromethorphan are rare, but nausea and/or other GI disturbances, slight drowsiness, and dizziness sometimes occur. The drug produces no analgesia or addiction and little or no CNS depression.

American Society of Health-System Pharmacists 2017; Drug Information 2017. Bethesda, MD. 2017, p. 2931


Although cough and cold preparations that contain cough suppressants (including dextromethorphan), nasal decongestants, antihistamines, and/or expectorants commonly are used in pediatric patients younger than 2 years of age, systematic reviews of controlled trials have concluded that nonprescription (over-the-counter, OTC) cough and cold preparations are not more effective than placebo in reducing acute cough and other symptoms of upper respiratory tract infection in these patients. Furthermore, adverse events, including deaths, have been (and continue to be) reported in pediatric patients younger than 2 years of age receiving these preparations.

American Society of Health-System Pharmacists 2017; Drug Information 2017. Bethesda, MD. 2017, p. 2931


For more Drug Warnings (Complete) data for Dextromethorphan (7 total), please visit the HSDB record page.


4.4 Drug Indication

Dextromethorphan is indicated in combination with [brompheniramine] and [pseudoephedrine] in the treatment of coughs and upper respiratory symptoms associated with allergies or the common cold. Dextromethorphan is also used in combination with [guaifenesin] as an over-the-counter product to relieve a cough. Dextromethorphan in combination with [quinidine] is indicated in the treatment of pseudobulbar affect.


5 Pharmacology and Biochemistry
5.1 Pharmacology

Dextromethorphan is an opioid-like molecule indicated in combination with other medication in the treatment of coughs and pseudobulbar affect. It has a moderate therapeutic window, as intoxication can occur at higher doses. Dextromethorphan has a moderate duration of action. Patients should be counselled regarding the risk of intoxication.


5.2 MeSH Pharmacological Classification

Antitussive Agents

Agents that suppress cough. They act centrally on the medullary cough center. EXPECTORANTS, also used in the treatment of cough, act locally. (See all compounds classified as Antitussive Agents.)


Excitatory Amino Acid Antagonists

Drugs that bind to but do not activate excitatory amino acid receptors, thereby blocking the actions of agonists. (See all compounds classified as Excitatory Amino Acid Antagonists.)


5.3 FDA Pharmacological Classification
5.3.1 Active Moiety
DEXTROMETHORPHAN
5.3.2 FDA UNII
7355X3ROTS
5.3.3 Pharmacological Classes
Sigma-1 Receptor Agonists [MoA]; Uncompetitive N-methyl-D-aspartate Receptor Antagonist [EPC]; Uncompetitive NMDA Receptor Antagonists [MoA]; Sigma-1 Agonist [EPC]
5.4 ATC Code

R05DA09

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355


R - Respiratory system

R05 - Cough and cold preparations

R05D - Cough suppressants, excl. combinations with expectorants

R05DA - Opium alkaloids and derivatives

R05DA09 - Dextromethorphan


5.5 Absorption, Distribution and Excretion

Absorption

A 30mg oral dose of dextromethorphan reaches a Cmax of 2.9 ng/mL, with a Tmax of 2.86 h, and an AUC of 17.8 ng\*h/mL.


Volume of Distribution

The volume of distribution of dextromethorphan is 5-6.7L/kg.


Dextromethorphan is rapidly absorbed from the GI tract and exerts its antitussive effect in 15-30 minutes after oral administration. The duration of action is approximately 3-6 hours with conventional dosage forms.

American Society of Health-System Pharmacists 2017; Drug Information 2017. Bethesda, MD. 2017, p. 2932


Dextromethorphan and its metabolites are excreted via the kidney. Depending on the metabolism phenotype up to 11% may be excreted unchanged or up to 100% as demethylated conjugated morphinan compounds. In the first 24 hours after dosing, less than 0.1% is eliminated in the feces.

International Programme on Chemical Safety; Poisons Information Monograph: Dextromethorphan (PIM 179) (1997). Available from, as of August 30, 2017: https://www.inchem.org/pages/pims.html


Dextromethorphan is well absorbed from the gastrointestinal tract with maximum serum level occurring at 2.5 hours. Peak concentration of the major metabolite dextrorphan) was 1.6 to 1.7 hours.

International Programme on Chemical Safety; Poisons Information Monograph: Dextromethorphan (PIM 179) (1997). Available from, as of August 30, 2017: https://www.inchem.org/pages/pims.html


Dextromethorphan hydrobromide (DM) is a widely used antitussive. This study determined, for the first time, the basic pharmacokinetic profile of DM and its active metabolite, dextrorphan (DP) in children and adolescents. Thirty-eight male and female subjects at risk for developing an upper respiratory tract infection (URTI), or symptomatic with cough due to URTI, were enrolled in this single-dose, open-label study: ages 2-5 years (Group A, n = 8), 6-11 years (Group B, n = 17), 12-17 years (Group C, n = 13). Subjects were genotyped for cytochrome P450 (CYP) 2D6 polymorphisms and characterized as poor (PM) or non-poor metabolizers (non-PM). Groups A and B were dosed using an age-weight dosing schedule (DM range 7.5-24.75 mg); a 30-mg dose was used for Group C. Average exposures to total DP increased as age group increased, and average exposure to DM was highest in the adolescent group. One subject in that group was a PM. The terminal half-life values were longer in the adolescent group due in part to the single PM subject. No relationship between body weight and pharmacokinetic parameters was noted. This is the first evaluation of the pharmacokinetic characteristics of DM in children and adolescents. A single dose of DM in this population was safe, and well tolerated at all doses tested. The data are used to model and compare pediatric DM exposures with those of adults.

PMID:25027615 Guenin E et al; Clin Drug Investig 34 (9): 609-16 (2014)


For more Absorption, Distribution and Excretion (Complete) data for Dextromethorphan (7 total), please visit the HSDB record page.


5.6 Metabolism/Metabolites

Dextromethorphan can be N-demethylated to 3-methoxymorphinan by CYP3A4, CYP2D6, and CYP2C9 or O-demethylated to dextrorphan by CYP2D6 and CYP2C9. Dextrorphan is N-demethylated by CYP3A4 and CYP2D6, while 3-methoxymorphinan is O-demethylated by CYP2D6. Both are metabolized to form 3-hydroxymorphinan. Dextrorphan and 3-hydroxymorphinan are both O-glucuronidated or O-sulfated.


Genetic polymorphism has profound effects on its metabolism. Dextromethorphan undergoes polymorphic metabolism depending on variation in cytochrome P-450 enzyme phenotype. The specific cytochrome P-450 enzyme is P450 2D6(CYP2D6). Fast metabolizers constitute about 84% of the population. After a 30 mg dose plasma levels are less than 5 ng/mL four hours postingestion. Intermediate metabolizers constitute about 6.8% of the population. After an oral dose of 30 mg plasma levels are 10 to 20 ng/mL at 4 hours and less than 5 ng/mL at 24 hours postingestion. Poor metabolizers constitute 5% to 10% of the Caucasian population. The ratio of metabolite to parent drug in 8 hour urine sample is less than 10 to 1 after a 15 mg dose. After an oral dose of 30 mg plasma levels are greater than 10 ng/mL at 4 hours and greater than 5 ng/mL at 24 hours.

International Programme on Chemical Safety; Poisons Information Monograph: Dextromethorphan (PIM 179) (1997). Available from, as of August 30, 2017: https://www.inchem.org/pages/pims.html


There is a clear first pass metabolism and it is generally assumed that the therapeutic activity is primarily due to its active metabolite, dextrophan.

International Programme on Chemical Safety; Poisons Information Monograph: Dextromethorphan (PIM 179) (1997). Available from, as of August 30, 2017: https://www.inchem.org/pages/pims.html


It is metabolized in the liver by extensive metabolizers to dextrorphan. Dextrorphan is itself an active antitussive compound. Only small amounts are formed in poor metabolizers. Less than 15% of the dose form minor metabolites including D-methoxymorphinane.

International Programme on Chemical Safety; Poisons Information Monograph: Dextromethorphan (PIM 179) (1997). Available from, as of August 30, 2017: https://www.inchem.org/pages/pims.html


The pentose phosphate pathway (PPP) is involved in the activity of glucose-6-phosphate dehydrogenase (G6PD) and generation of NADPH, which plays a key role in drug metabolism. The aim of this study was to investigate the effects of modulation of the PPP on drug metabolism capacity in vitro. A pair of hepatic cell lines, ie, the cancerous HepG2 cells and normal L02 cells, was used. The expression of CYP450 enzymes, p53 and G6PD in the cells were analyzed. The metabolism of testosterone (TEST, 10 umol/L) and dextromethorphan (DEM, 1 umol/L), the two typical substrates for CYP3A4 and CYP2D6, in the cells was examined in the presence of different agents. Both the expression and metabolic activities of CYP3A4 and CYP2D6 were considerably higher in HepG2 cells than in L02 cells. The metabolism of TEST and DEM in HepG2 cells was dose-dependently inhibited by the specific CYP3A4 inhibitor ketoconazole and CYP2D6 inhibitor quinidine. Addition of the p53 inhibitor cyclic PFT-alpha (5, 25 umol/L) in HepG2 cells dose-dependently enhanced the metabolism of DEM and TEST, whereas addition of the p53 activator NSC 66811 (3, 10, 25 umol/L) dose-dependently inhibited the metabolism. Furthermore, addition of the G6PD inhibitor 6-aminonicotinamide (5, 15 umol/L) in HepG2 cells dose-dependently inhibited the metabolism of DEM and TEST, whereas addition of the PPP activity stimulator menadione (1, 5, 15 umol/L) dose-dependently enhanced the metabolism. Modulation of p53 and the PPP alters the metabolism of DEM and TEST, suggesting that the metabolic flux pattern of PPP may be closely involved in drug metabolism and the individual variance.

PMID:25619394 Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326794 Xiao WJ et al; Acta Pharmacol Sin 36 (2): 259-67 (2015)


Dextromethorphan has known human metabolites that include 3-methoxymorphinan and Dextrorphan.

S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560


5.7 Biological Half-Life

Dextromethorphan has a half life of 3-30 hours.


The half life of /dextromethorphan/ is approximately 2 to 4 hours in people with normal metabolism.

International Programme on Chemical Safety; Poisons Information Monograph: Dextromethorphan (PIM 179) (1997). Available from, as of August 30, 2017: https://www.inchem.org/pages/pims.html


5.8 Mechanism of Action

Dextromethorphan is an agonist of NMDA and sigma-1 receptors. It is also an antagonist of 3/4 nicotinic receptors. However, the mechanism by which dextromethorphan's receptor agonism and antagonism translates to a clinical effect is not well understood.


Dextromethorphan (DXM) is the dextro isomer of levomethorphan, a semisynthetic morphine derivative. Although structurally similar to other /CNS depressants/, DXM does not act as a mu receptor opioid (eg, morphine, heroin). DXM and its metabolite, dextrorphan, act as potent blockers of the N-methyl-d-aspartate (NMDA) receptor.

Department of Justice; Drug Enforcement Administration (DEA), Dextromethorphan (March 2014). Available from, as of August 30, 2017: https://www.deadiversion.usdoj.gov/drug_chem_info/dextro_m.pdf


Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson's disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT(1A) receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT(1A) agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT(1A) antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT(1A) agonism. Combined with previous work from our group, our results support the investigation of 5-HT(1A) agonists as pharmacotherapies for LID in PD patients.

PMID:22861201 Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573705 Paquette MA et al; Eur J Neurosci 36 (9): 3224-34 (2012)


Dextromethorphan (DM) is a dextrorotatory morphinan and an over-the-counter non-opioid cough suppressant. We have previously shown that DM protects against LPS-induced dopaminergic neurodegeneration through inhibition of microglia activation. Here, we investigated protective effects of DM against endotoxin shock induced by lipopolysaccharide/d-galactosamine (LPS/GalN) in mice and the mechanism underlying its protective effect. Mice were given multiple injections of DM (12.5 mg/kg, s.c.) 30 min before and 2, 4 hr after an injection of LPS/GalN (20 ug/700 mg/kg). DM administration decreased LPS/GalN-induced mortality and hepatotoxicity, as evidenced by increased survival rate, decreased serum alanine aminotransferase activity and improved pathology. Furthermore, DM was also effective when it was given 30 min after LPS/GalN injection. The protection was likely associated with reduced serum and liver tumor necrosis factor alpha (TNF-alpha) levels. DM also attenuated production of superoxide and intracellular reactive oxygen species in Kupffer cells and neutrophils. Real-time RT-PCR analysis revealed that DM administration suppressed the expression of a variety of inflammation-related genes such as macrophage inflammatory protein-2, CXC chemokine, thrombospondin-1, intercellular adhesion molecular-1 and interleukin-6. DM also decreased the expression of genes related to cell-death pathways, such as the DNA damage protein genes GADD45 and GADD153. In summary, DM is effective in protecting mice against LPS/GalN-induced hepatotoxicity, and the mechanism is likely through a faster TNF-alpha clearance, and decrease of superoxide production and inflammation and cell-death related components. This study not only extends neuroprotective effect of DM, but also suggests that DM may be a novel compound for the therapeutic intervention for sepsis.

PMID:15627475 Li G et al; Biochem Pharmacol 69 (2): 233-40 (2005)


/The investigators/ showed that dextromethorphan (DM) provides neuroprotective/anticonvulsant effects and that DM and its major metabolite, dextrorphan /DX/, have a high-affinity for sigma(1) receptors, but a low affinity for sigma(2) receptors. In addition, we found that DM has a higher affinity than DX for sigma(1) sites, whereas DX has a higher affinity than DM for PCP sites. We extend our earlier findings by showing that DM attenuated trimethyltin (TMT)-induced neurotoxicity (convulsions, hippocampal degeneration and spatial memory impairment) in rats. This attenuation was reversed by the sigma(1) receptor antagonist BD 1047, but not by the sigma(2) receptor antagonist ifenprodil. DM attenuates TMT-induced reduction in the sigma(1) receptor-like immunoreactivity of the rat hippocampus, this attenuation was blocked by the treatment with BD 1047, but not by ifenprodil. These results suggest that DM prevents TMT-induced neurotoxicity, at least in part, via sigma(1) receptor stimulation.

PMID:17386960 Shin EJ et al; Neurochem Int 50 (6): 791-9 (2007)


Dextromethorphan (DEX) is a widely used non-opioid antitussive. However, the precise site of action and its mechanism were not fully understood. We examined the effects of DEX on AMPA receptor-mediated glutamatergic transmission in the nucleus tractus solitarius (NTS) of guinea pigs. Excitatory postsynaptic currents (evoked EPSCs: eEPSCs) were evoked in the second-order neurons by electrical stimulation of the tractus solitarius. DEX reversibly decreased the eEPSC amplitude in a concentration-dependent manner. The DEX-induced inhibition of eEPSC was accompanied by an increased paired-pulse ratio. Miniature EPSCs (mEPSCs) were also recorded in the presence of Cd(2+) or tetrodotoxin. DEX decreased the frequency of mEPSCs without affecting their amplitude. Topically applied AMPA provoked an inward current in the neurons, which was unchanged during the perfusion of DEX. BD1047, a sigma-1-receptor antagonist, did not block the inhibitory effect of DEX on the eEPSCs, but antagonized the inhibition of eEPSCs induced by SKF-10047, a sigma-1 agonist. Haloperidol, a sigma-1 and -2 receptor ligand, had no influence on the inhibitory action of DEX. These results suggest that DEX inhibits glutamate release from the presynaptic terminals projecting to the second-order NTS neurons, but this effect of DEX is not mediated by the activation of sigma receptors.

PMID:21487194 Ohi Y et al; J Pharmacol Sci 116 (1): 54-62 (2011)


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08-Jan-2021
31-Aug-2024
KGS
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