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