Amitifadine Explained

Amitifadine (developmental code names DOV-21,947, EB-1010) is a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) or so-called triple reuptake inhibitor (TRI) which is or was being developed by Euthymics Bioscience^{[1] [2]} It was under development for the treatment of major depressive disorder, but in May 2013, it was reported that the drug failed to show superior efficacy to placebo in a phase IIb/IIIa clinical trial.^[3] 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 and smoking withdrawal.

Pharmacology

K_i values for SERT, NET, and DAT of amitifadine are 99 nM, 262 nM, and 213 nM.^[2] The IC₅₀ values for serotonin, norepinephrine and dopamine uptake are 12, 23 and 96 nM, respectively

Amitifadine and isomers

Compound	Uptake (IC50, nM)			Binding (Ki, nM)
	5-HT	NE	DA	SERT	NET	DAT
Amitifadine	12	23	96	100	260	210
DOV-216,303	14	20	78	190	380	190
DOV-102,677	130	100	130	740	1000	220

Amitifadine reduces the duration of immobility in the forced swim test 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, 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.^[4] Results in a small clinical trial indicated that amitifadine had statistically significant antidepressant effects and was well tolerated.^[5]

Chemistry

Amitifadine is the (+)-enantiomer 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.

External links

• Amitifadine Euthymics Bioscience

Notes and References

1. Web site: Amitifadine. AdisInsight. 26 February 2017. en.
2. Skolnick P, Popik P, Janowsky A, Beer B, Lippa AS . Antidepressant-like actions of DOV 21,947: a "triple" reuptake inhibitor . European Journal of Pharmacology . 461 . 2–3 . 99–104 . February 2003 . 12586204 . 10.1016/S0014-2999(03)01310-4 .
3. Web site: Euthymics Reports Top-Line Results From Triade Trial of Amitifadine for Major Depressive Disorder . Cambridge, MA . May 29, 2013 . Euthymics Bioscience, Inc. . 2017-06-12 . https://web.archive.org/web/20170924095823/http://euthymics.com/wp-content/uploads/2013/05/FINAL_Euthymics_TRIADE_Results_052913.pdf . 2017-09-24 . dead .
4. Golembiowska K, Kowalska M, Bymaster FP . Effects of the triple reuptake inhibitor amitifadine on extracellular levels of monoamines in rat brain regions and on locomotor activity . Synapse . 66 . 5 . 435–44 . May 2012 . 22213370 . 10.1002/syn.21531 . 32581051 .
5. Tran P, Skolnick P, Czobor P, Huang NY, Bradshaw M, McKinney A, Fava M . Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial . Journal of Psychiatric Research . 46 . 1 . 64–71 . January 2012 . 21925682 . 10.1016/j.jpsychires.2011.09.003 . free .