Bromantane

Clinical data
Trade names	Ladasten
Other names	Bromantan; Bromontan; ADK-709;N-(2-Adamantyl)-4-bromoaniline;N-(2-Adamantyl)-N-(4-Bromophenyl)amine;N-(4-Bromophenyl)-2-adamantanamine
Routes of administration	By mouth
ATC code	None
Legal status
Legal status	US: Unscheduled, not FDA approved Rx-only(RU)
Pharmacokinetic data
Bioavailability	42%[1]
Onset of action	1.5–2 hours (PO)
Eliminationhalf-life	11.21 hours (in humans),[2] 7 hours (in rats)[3]
Duration of action	8–12 hours (PO)
Identifiers
IUPAC name N-(4-Bromophenyl)adamantan-2-amine
CAS Number	87913-26-6 Y
PubChemCID	4660557
ChemSpider	3849628 Y
UNII	N1ILS53XWK
CompTox Dashboard(EPA)	DTXSID40405333
ECHA InfoCard	100.213.907
Chemical and physical data
Formula	C16H20BrN
Molar mass	306.247 g·mol−1
3D model (JSmol)	Interactive image
SMILES Brc1ccc(NC2C3CC4CC(C3)CC2C4)cc1
InChI 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
(verify)

Bromantane, sold under the brand nameLadasten, is an atypicalcentral nervous system (CNS)stimulant andanxiolytic drug of theadamantane family that is related toamantadine andmemantine. Medically, it is approved in Russia for the treatment ofneurasthenia. Although the effects of bromantane have been determined to be dependent on thedopaminergic and possiblyserotonergicneurotransmitter systems, its exactmechanism of action is unknown,^[4][5] and is distinct in its properties relative to typical stimulants such asamphetamine. Bromantane has sometimes been described as anactoprotector (synthetic adaptogen).^[6][7]

The therapeutic effects of bromantane in asthenia are said to onset within 1–3 days.^[8] It has been proposed that the combination of stimulant and anxiolytic activity may give bromantane special efficacy in the treatment of asthenia.^[9]

In a large-scale, multi-centerclinical trial of 728 patients diagnosed withasthenia in Russia, bromantane was given for 28 days at a daily dose of 50 mg or 100 mg.^[8] The study concluded with an impression score of 76.0% on theCGI-S and 90.8% on theCGI-I for bromantane, indicating that it is broadly applicable and highly effective.^[8] The therapeutic benefit against asthenia was observed to still be present one month after discontinuation of the drug.^[8] 3% of patients experienced side effects; though none were considered serious; and 0.8% of patients discontinued treatment due to side effects.^[8] Bromantane was also noted to normalize thesleep-wake cycle.^[8]

Bromantane is described primarily as a mild stimulant^[10] and anxiolytic.^[9] It is also said to possess anti-asthenic properties.^[11][9] Bromantane is reported to improve physical and mental performance, hence it could be considered aperformance-enhancing drug.^[11]

Bromantane has been found to lower the levels ofpro-inflammatory cytokinesIL-6,IL-17 andIL-4 and to normalize behavior in animal models ofdepression, and may possess clinical efficacy as anantidepressant.^[12][13][14] It has also been found to increase sexual receptivity and proceptivity in rats of both sexes, which was attributed to its dopaminergic actions.^[15] It has been proposed that bromantane may suppressprolactin levels by virtue of its dopaminergic properties as well.^[16] Bromantane has been found to "agonize" amphetamine-induced stereotypiesin vivo, suggesting that it might potentiate certain effects of other stimulants.^[5]

The stimulant effects of bromantane onset gradually within 1.5–2 hours and last for 8–12 hours when takenorally.^[10]

Although it is frequently labeled as a stimulant, bromantane is distinct in itspharmacology and effects relative to typical stimulants, such as thephenethylamines (e.g.,amphetamine and its derivatives) and theirstructural analogues (e.g.,methylphenidate,cocaine,mesocarb, etc.).^[17][18] Whereas the latter directly act on thedopamine transporter (DAT) toinhibit thereuptake and/orinduce therelease of dopamine, bromantane instead acts via indirectgenomic mechanisms to produce a rapid, pronounced, and long-lastingupregulation in a variety of brain regions of theexpression oftyrosine hydroxylase (TH) andaromaticL-amino acid decarboxylase (AAAD) (also known as DOPA decarboxylase), keyenzymes in the dopaminebiosynthesis pathway.^[10][19][20] For instance, a single dose of bromantane produces a 2–2.5 fold increase in TH expression in the rathypothalamus 1.5–2 hours post-administration.^[21] The biosynthesis and release of dopamine subsequently increase in close correlation with TH and AAAD upregulation.^[10][19][20] Enhancement of dopaminergicneurotransmission is observed in the hypothalamus,striatum,ventral tegmental area,nucleus accumbens, and other regions.^[10][19][20] As such, the key mechanism of the pharmacological activity and psychostimulant effects of bromantane is activation of thede novo synthesis of dopamine via modulation of gene expression.^[19]

A selection of quoted excerpts from the medical literature detail the differences between bromantane and typical stimulants:^[11][10][17]

• "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 fewside effects (including peripheral sympathomimetic effects and hyperstimulation), does not appear to producetolerance ordependence, has not been associated withwithdrawal symptoms upon discontinuation, and displays an absence ofaddiction potential, contrary to typical stimulants.^[11][9] In accordance with human findings, animals exposed to bromantane for extended periods of time do not appear to develop tolerance or dependence.^[22]

The precise direct molecularmechanism of action by which bromantane ultimately acts as a dopamine synthesis enhancer is unknown.^[4][5] However, it has been determined that activation of certaincAMP-,Ca²⁺-, andphospholipid-dependentprotein kinases such asprotein kinase A and especiallyprotein kinase C corresponds with the manifestation of the pharmacological effects of bromantane.^[18][23] Bromantane may activate intracellular signaling cascades by some mechanism (e.g.,agonizing some as-yet-undeterminedreceptor) to in turn activate protein kinases, which in turn cause increasedtranscription of TH and AAAD.^[18][23]

The related drugs amantadine and memantine also have many properties similar to those of bromantane.^[24][25][26]

Researchers discovered thatamantadine andmemantine bind to and act asagonists of theσ₁ receptor (K_i = 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.

Bromantane was once thought to act as a reuptake inhibitor of serotonin and dopamine.^[4][17][27] While bromantane can inhibit the reuptake of serotonin, dopamine, and to a lesser extentnorepinephrinein vitro in rat brain tissue, the concentrations required to do so are extremely high (50–500 μM) and likely not clinically relevant.^[17][27] Although one study found anIC₅₀ 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.^[28] The lack of typical stimulant-like effects and adverse effects seen with bromantane may help corroborate the notion that it is not acting significantly as amonoamine reuptake inhibitor, but rather via a different mechanism.

Bromantane has been found to increase the expression ofneurotrophins includingbrain-derived neurotrophic factor andnerve growth factor in certain rat brain areas.^[29]

Although not relevant at clinical dosages, bromantane has been found to produceanticholinergic effects, including bothantimuscarinic andantinicotinic actions, at very high doses in animals, and these effects are responsible for itstoxicity (that is,LD₅₀) in animals.^{[27][30][31][32]}

Bromantane is used clinically in doses of 50 mg to 100 mg per day in the treatment of asthenia.^[8]

The rate of absorption in women is greater than in men, with maximum blood concentrations being reached at 2.75 and 4 hours after oral administration, respectively.^[11]

The mainmetabolite of bromantane is 6β-hydroxybromantane.^[33]

Bromantane is anadamantanederivative. It is also known as adamantylbromphenylamine, from which its name was derived.^[2]

Closely relatedadamantanes with similar effects includeadapromine,amantadine,chlodantane,gludantane (gludantan),memantine, andrimantadine.^[24]

TheLeuckart reaction betweenadamantanone and4-bromoaniline in the presence offormic acid produces bromantane.

In the 1960s, the adamantane derivativeamantadine (1-aminoadamantane) was developed as anantiviral drug for the treatment ofinfluenza.^[37] Other adamantane antivirals subsequently followed, such asrimantadine (1-(1-aminoethyl)adamantane) andadapromine (1-(1-aminopropyl)adamantane).^[6][37] It was serendipitously discovered in 1969 that amantadine possesses centraldopaminergic stimulant-like properties,^[38][39] and subsequent investigation revealed that rimantadine and adapromine also possess such properties.^[40] Amantadine was then developed and introduced for the treatment ofParkinson's disease due to its ability to increasedopamine levels in the brain.^[38] It has also notably since been used to help alleviatefatigue inmultiple sclerosis.^[41]

With the knowledge of the dopaminergic stimulant effects of the adamantane derivatives, bromantane, which is 2-(4-bromophenylamino) adamantane, was developed in the 1980s at the Zakusov State Institute of Pharmacology,USSR Academy of Medical Sciences (now the Russian Academy of Medical Sciences) inMoscow as "a drug having psychoactivating and adaptogen properties under complicated conditions (hypoxia, high environmental temperature, physical overfatigue, emotional stress, etc.)".^[11][5] It was found to produce more marked and prolonged stimulant effects than the other adamantanes,^[42] and eventually entered use.^[11] The drug was notably given to soldiers in the Soviet and Russian militaries to "shorten recovery times after strong physical exertion".^[11] After the break-up of theSoviet Union in 1991, bromantane continued to be researched and characterized but was mainly limited in use tosports medicine (for instance, to enhance athletic performance).^[11] In 1996, it was encountered as adoping agent in the1996 Summer Olympics when several Russian athletes tested positive for it, and was subsequently placed on theWorld Anti-Doping Agency banned list in 1997 as a stimulant andmasking agent.^[11][43]

Bromantane was eventually repurposed in 2005 as a treatment forneurasthenia.^[44] It demonstrated effectiveness and safety for the treatment of the condition in extensive, large-scaleclinical trials,^[8] and was approved for this indication in Russia under the brand name Ladasten sometime around 2009.^[9]

• List of Russian drugs

• Media related toBromantane at Wikimedia Commons

• Drugs not assigned an ATC code
• Adamantanes
• Anilines
• Antidepressants
• Anxiolytics
• Aphrodisiacs
• 4-Bromophenyl compounds
• Dopamine reuptake inhibitors
• Drugs in the Soviet Union
• Drugs with unknown mechanisms of action
• Nootropics
• Russian drugs
• Russian inventions
• Stimulants
• World Anti-Doping Agency prohibited substances

• CS1 Russian-language sources (ru)
• Articles with short description
• Short description is different from Wikidata
• Drugs with non-standard legal status
• ECHA InfoCard ID from Wikidata
• Articles with changed InChI identifier
• Articles without EBI source
• Chemical pages without DrugBank identifier
• Articles without KEGG source
• Commons category link from Wikidata