Amitifadine (developmental code names DOV-21,947, EB-1010) is a
serotonin–norepinephrine–dopamine reuptake inhibitor
A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and d ...
(SNDRI) or so-called triple reuptake inhibitor (TRI) which is or was being developed by
Euthymics Bioscience It was under development for the treatment of
major depressive disorder
Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
, but in May 2013, it was reported that the drug failed to show superior
efficacy to
placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures.
In general ...
in a
phase IIb
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
/
IIIa clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
.
It was suggested that this may have been due to the drug being underdosed.
In September 2017, development of amitifadine for the treatment of major depressive disorder was finally officially discontinued.
As of September 2017, it is still listed as being under development for the treatment of
alcoholism
Alcoholism is, broadly, any drinking of alcohol that results in significant mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognized diagnostic entity. Predomina ...
and
smoking withdrawal
Smoking cessation, usually called quitting smoking or stopping smoking, is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is addictive and can cause dependence. As a result, nicotine withdrawal often make ...
.
Pharmacology
K
i values for
SERT,
NET, and
DAT of amitifadine are 99 nM, 262 nM, and 213 nM.
The
IC50 values for
serotonin,
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...
and
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...
uptake are 12, 23 and 96 nM, respectively
Amitifadine reduces the duration of immobility in the
forced swim test
The behavioural despair test (or Porsolt forced swimming test) is a test, centered on a rodent's response to the threat of drowning, whose result has been interpreted as measuring susceptibility to negative mood. It is commonly used to measure the ...
in rats with an oral
minimum effective dose (MED) of 5 mg/kg. This antidepressant-like effect manifests in the absence of significant increases in motor activity at doses of up to 20 mg/kg. Amitifadine also produces a dose-dependent reduction in immobility in the
tail suspension test
The tail suspension test (TST) is an experimental method used in scientific research to measure stress in rodents. It is based on the observation that if a mouse is subjected to short term inescapable stress then the mouse will become immobil ...
, with an oral MED of 5 mg/kg. In microdialysis studies, amitifadine increased extracellular levels of serotonin, norepinephrine and dopamine in brain regions and did not induce hyperactivity in rats.
Results in a small clinical trial indicated that amitifadine had statistically significant antidepressant effects and was well tolerated.
Chemistry

Amitifadine is the (+)-
enantiomer
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
of
DOV-216,303, and its (−)-enantiomer is
DOV-102,677.
Amitifadine is very similar in structure to
Bicifadine &
Centanafadine.
A so-called "bifunctional molecule" from a separate organization called GSK 598809 has related structure.
References
External links
Amitifadine Euthymics Bioscience
{{Monoamine reuptake inhibitors
Abandoned drugs
Antidepressants
Chloroarenes
Experimental drugs
Serotonin–norepinephrine–dopamine reuptake inhibitors