Amitifadine

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.[3] In September 2017, development of amitifadine for the treatment of major depressive disorder was finally officially discontinued.[1] As of September 2017, it is still listed as being under development for the treatment of alcoholism and smoking withdrawal.[1]

Amitifadine
Clinical data
Pronunciation(/æmɪˈtɪfədiːn/ am-i-TIF-ə-deen)
Other namesDOV-21,947; EB-1010
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC11H11Cl2N
Molar mass228.118 g/mol g·mol−1
3D model (JSmol)
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Pharmacology

Ki 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
DOV stereochemistry

Amitifadine is the (+)-enantiomer of DOV-216,303, and its (−)-enantiomer is DOV-102,677.

References
  1. "Amitifadine". AdisInsight. Retrieved 26 February 2017.
  2. Skolnick, P.; Popik, P.; Janowsky, A.; Beer, B.; Lippa, A. S. (2003). "Antidepressant-like actions of DOV 21,947: a "triple" reuptake inhibitor". European Journal of Pharmacology. 461 (2–3): 99–104. doi:10.1016/S0014-2999(03)01310-4. PMID 12586204.
  3. "Archived copy" (PDF). Archived from the original (PDF) on 2017-09-24. Retrieved 2017-06-12.CS1 maint: archived copy as title (link)
  4. Golembiowska, K.; Kowalska, M.; Bymaster, F. P. (2012). "Effects of the triple reuptake inhibitor amitifadine on extracellular levels of monoamines in rat brain regions and on locomotor activity". Synapse. 66 (5): 435–444. doi:10.1002/syn.21531. PMID 22213370.
  5. Tran, P.; Skolnick, P.; Czobor, P.; Huang, N. Y.; Bradshaw, M.; McKinney, A.; Fava, M. (2012). "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. doi:10.1016/j.jpsychires.2011.09.003. PMID 21925682.
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