Bromantane

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Bromantane
Clinical data
Trade namesLadasten
Other namesBromantan; Bromontan; ADK-709; Adamantylbromphenylamine
Routes of
administration		Oral (tablets)
ATC code
  • None
Legal status
Legal status
  • US: Unscheduled not FDA approved
  • Rx-only (RU)
Pharmacokinetic data
Bioavailability27.5%
Elimination half-life11.21 hours (in humans),[1]
7 hours (in rats)[2]
Identifiers
  • N-(4-Bromophenyl)adamantan-2-amine
JSmol)
  • C1C2CC3CC1CC(C2)C3NC4=CC=C(C=C4)Br
  • InChI=1S/C16H20BrN/c17-14-1-3-15(4-2-14)18-16-12-6-10-5-11(8-12)9-13(16)7-10/h1-4,10-13,16,18H,5-9H2 ☒N
  • Key:LWJALJDRFBXHKX-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Bromantane, sold under the brand name Ladasten, is an atypical

psychostimulant and anxiolytic drug of the adamantane family related to amantadine and memantine which is used in Russia in the treatment of neurasthenia. Although the effects of the bromantane have been determined to be dependent on the dopaminergic and possibly serotonergic neurotransmitter systems, its exact mechanism of action is unknown,[3][4] and it is distinct in its properties relative to typical psychostimulants such as amphetamine. Because of its unique aspects, bromantane has sometimes been described instead as an actoprotector.[5][6]

Medical uses

Clinical research

The therapeutic effects of bromantane in asthenia are said to onset within 1- to 3-days.[7] It has been proposed that the combination of psychostimulant and anxiolytic activity may give bromantane special efficacy in the treatment of asthenia.[8]

In a large-scale, multi-center

sleep-wake cycle.[7] The authors concluded that "[Bromantane] in daily dose from 50 to 100 mg is a highly effective, well-tolerated and [safe] drug with a wide spectrum of clinical effects. Therefore, this drug could be recommended for treatment of asthenic disorders in neurological practice."[7]

Effects

Bromantane is described primarily as a mild psychostimulant

performance-enhancing drug.[10]

Bromantane has been found to lower the levels of

pro-inflammatory cytokines IL-6, IL-17 and IL-4 and to normalize behavior in animal models of depression, and may possess clinical efficacy as an antidepressant.[11][12][13] It has also been found to increase sexual receptivity and proceptivity in rats of both sexes, which was attributed to its dopaminergic actions.[14] It has been proposed that bromantane may suppress prolactin levels by virtue of its dopaminergic properties as well.[15] Bromantane has been found to "agonize" amphetamine-induced stereotypies in vivo, suggesting that it might potentiate certain effects of other psychostimulants.[4]

The psychostimulant effects of bromantane onset gradually within 1.5- to 2-hours and last for 8- to 12-hours.[9]

Pharmacology

Pharmacodynamics

Dopamine synthesis enhancement

Although it is frequently labeled as a psychostimulant, bromantane is distinct in its

genomic mechanisms to produce a rapid, pronounced, and long-lasting upregulation in a variety of brain regions of the expression of tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AAAD) (also known as DOPA decarboxylase), key enzymes in the dopamine biosynthesis pathway.[9][18][19] For instance, a single dose of bromantane produces a 2- to 2.5-fold increase in TH expression in the rat hypothalamus 1.5- to 2-hours post-administration.[20] The biosynthesis and release of dopamine subsequently increase in close correlation with TH and AAAD upregulation.[9][18][19] Enhancement of dopaminergic neurotransmission is observed in the hypothalamus, striatum, ventral tegmental area, nucleus accumbens, and other regions.[9][18][19] As such, the key mechanism of the pharmacological activity and psychostimulant effects of bromantane is activation of the de novo synthesis of dopamine via modulation of gene expression.[18]

A selection of quoted excerpts from the medical literature detail the differences between bromantane and typical psychostimulants:[10][9][16]

  • "Bromantane [does] not concede well-known psychostimulant of phenylalkylamine structure and its analogs (amphetamine, [mesocarb], [methylphenidate], etc.) by specific activity. In contrast, bromantane has neither addictive potential nor reveals redundant and exhausting activation of sympaticoadrenergic system, or decelerates the restoring of work capacity at preventive application before forthcoming activity in complicated conditions (hypoxia, high environmental temperature, physical overfatigue, emotional stress, etc.). Bromantane has no prohypoxic activity."
  • "The use of the drug, in contrast to the action of a typical psychostimulant, is not associated with the phenomenon of hyperstimulation and causes no consequences such as functional exhaustion of the body."
  • "Bromantane administration in therapeutic doses is characterized by the almost full absence of side effects including manifestations of withdrawal syndrome and hyperstimulation."
  • "[Bromantane] has low peripheral sympathomimetic effects. Moreover, no signs of [bromantane] dependence and withdrawal symptoms were found."

Bromantane is well tolerated and elicits few

addiction potential, contrary to typical psychostimulants.[10][8] In accordance with human findings, animals exposed to bromantane for extended periods of time do not appear to develop tolerance or dependence.[21]

The precise direct molecular

transcription of TH and AAAD.[17][22]

Researchers discovered that amantadine and memantine bind to and act as agonists of the σ1 receptor (Ki = 7.44 μM and 2.60 μM, respectively) and that activation of the σ1 receptor is involved in the central dopaminergic effects of amantadine at therapeutically relevant concentrations; the authors of the study stated that this could also be the mechanism of action of bromantane, as it is in the same family of structurally related compounds and evidence suggests a role of dopamine in its effects. But this could also be seen as evidence of the contrary since bromantane has effects that are distinctly different from amantadine and memantine.

Monoamine reuptake inhibition

Bromantane was once thought to act as a reuptake inhibitor of serotonin and dopamine.[3][16][23] While bromantane can inhibit the reuptake of serotonin, dopamine, and to a lesser extent norepinephrine in vitro in rat brain tissue, the concentrations required to do so are extremely high (50–500 μM) and likely not clinically relevant.[16][23] Although one study found an IC50 for dopamine transport of 3.56 μM, relative to 28.66 nM for mesocarb; neither drug affected serotonin transport at the tested concentrations, in contrast.[24] The lack of typical psychostimulant-like effects and adverse effects seen with bromantane may help corroborate the notion that it is not acting significantly as a monoamine reuptake inhibitor, but rather via enhancement of dopamine synthesis.

Other actions

Bromantane has been found to increase the expression of neurotrophins including brain-derived neurotrophic factor and nerve growth factor in certain rat brain areas.[25]

Although not relevant at clinical dosages, bromantane has been found to produce

LD50) in animals.[23][26][27][28]

Pharmacokinetics

Bromantane is used clinically in doses of 50 mg to 100 mg per day in the treatment of asthenia.[7]

The main metabolite of bromantane is 6β-hydroxybromantane.[29]

Chemistry

Bromantane is an

derivative. It is also known as adamantylbromphenylamine, from which its name was derived.[1]

History

In the 1960s, the adamantane derivative

fatigue in multiple sclerosis.[34]

With the knowledge of the dopaminergic psychostimulant effects of the adamantane derivatives, bromantane, which is 2-(4-bromophenylamino)adamantane, was developed in the 1980s at the Zakusov State Institute of Pharmacology,

doping agent in the 1996 Summer Olympics when several Russian athletes tested positive for it, and was subsequently placed on the World Anti-Doping Agency banned list in 1997 as a stimulant and masking agent.[10][36]

Bromantane was eventually repurposed in 2005 as a treatment for neurasthenia.[37] It demonstrated effectiveness and safety for the treatment of the condition in extensive, including large-scale clinical trials,[7] and was approved for this indication in Russia under the brand name Ladasten sometime around 2009.[8]

Synthesis

Patents:[38][39] 57%:[40]

The reductive amination between Adamantanone [700-58-3] and 4-Bromoaniline [106-40-1] in the presence of formic acid gave bromantane (3).

See also

References

  1. ^ a b "Ladasten (adamantylbromphenylamine) Tablets for Oral Use. Full Prescribing Information". Russian State Register of Medicines (in Russian). Lekko CJSC. p. 1. Archived from the original on 3 February 2016. Retrieved 27 January 2016.
  2. S2CID 40317188
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  3. ^
    S2CID 33214442
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  4. ^
    PMID 11348840
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  5. ^
    S2CID 41620120
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  6. S2CID 29475883
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  7. ^
    PMID 21322821
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  8. ^
    PMID 19491814
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  9. ^
    S2CID 43661752
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  10. ^
    PMID 24009833
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  11. PMID 22288152
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  12. S2CID 23634912
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  13. S2CID 13007622
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  14. PMID 15341065
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  15. PMID 10650526
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  16. ^
    PMID 11348840
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  17. ^
    S2CID 39459723
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  18. ^
    PMID 15500036
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  19. ^
    S2CID 28048257
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  20. PMID 16915929
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  21. PMID 11109517
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  22. ^
    PMID 15188752
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  23. ^
    PMID 10198757
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  24. PMID 20369592
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  25. S2CID 15466533
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  26. PMID 10763112
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  27. S2CID 3050185
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  28. S2CID 3050185
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  29. PMID 22250799
    .
  30. ^
    ISBN 978-0-340-81694-3
    .
  31. ^
    ISBN 978-0-12-125831-3
    .
  32. ISBN 978-1-4200-7352-2
    .
  33. S2CID 21940190
    .
  34. ISBN 978-1-58562-216-0
    .
  35. S2CID 34884133
    .
  36. S2CID 34909949
    .
  37. PMID 16995430
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  38. ^ RU 1601978, Klimova NV, Zaitseva NM, Pushkartin GV, Pyatin BM, Morozovk IS, Kislyak NA, Shcherbakova OV, Bykov NP, "Method of synthesis of n-(4-bromophenyl)-n-(2-adamantyl)amine", issued 27 October 1995 
  39. ^ RU 860446, Waldman AV, Zaitseva NM, Klimova NV, Lavrova LN, Morozovn IS, Shmar MI, Shcherbakova OV, Yakubov AA, Strekalova SN, Petukhov AG, "Substituted n-adamantilanilines possessing psychostimulating activity", issued 1993, assigned to Cherkasskij Z Khimreaktivov 
  40. S2CID 85441518
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External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Bromantane&oldid=1219604697"