Pharmacodynamics Dopamine synthesis enhancement Although it is frequently labeled as a stimulant, bromantane is distinct in its
pharmacology and effects relative to typical stimulants, such as the
phenethylamines (e.g.,
amphetamine and its derivatives) and their
structural analogues (e.g.,
methylphenidate,
cocaine,
mesocarb, etc.). Whereas the latter directly act on the
dopamine transporter (DAT) to
inhibit the
reuptake and/or
induce the
release of dopamine, bromantane instead acts via indirect
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. For instance, a single dose of bromantane produces a 2–2.5 fold increase in TH expression in the rat
hypothalamus 1.5–2 hours post-administration. The biosynthesis and release of dopamine subsequently increase in close correlation with TH and AAAD upregulation. The precise direct molecular
mechanism of action by which bromantane ultimately acts as a dopamine synthesis enhancer is unknown. Bromantane may activate intracellular signaling cascades by some mechanism (e.g.,
agonizing some as-yet-undetermined
receptor) to in turn activate protein kinases, which in turn cause increased
transcription of TH and AAAD. 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. 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. 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 a
monoamine reuptake inhibitor, but rather via a different mechanism.
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. Although not relevant at clinical dosages, bromantane has been found to produce
anticholinergic effects, including both
antimuscarinic and
antinicotinic actions, at very high doses in animals, and these effects are responsible for its
toxicity (that is,
LD50) in animals.
Pharmacokinetics Bromantane is used clinically in doses of 50 mg to 100 mg per day in the treatment of asthenia. ==Chemistry==