Amitifadine
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| Pronunciation | (/æmɪˈtɪfədiːn/ am-i-TIF-ə-deen) |
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| Synonyms | DOV-21,947; EB-1010 |
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| Formula | C11H11Cl2N |
| Molar mass | 228.118 g/mol |
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Amitifadine (DOV-21,947 or EB-1010)[1] is an antidepressant drug being developed by Euthymics Bioscience Inc.[2] It is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) or so-called triple reuptake inhibitor (TRI).[2] Although amitifadine is still said to be under development for the treatment of major depressive disorder, no new development has been reported since 2013.[3] In the last development update, which was in May 2013, it failed to demonstrate superior efficacy to placebo in a phase IIb/IIIa clinical trial, perhaps due to having been underdosed.[4]
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
| Compound | Uptake | Binding | ||||
|---|---|---|---|---|---|---|
| 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.[5] Results in a small clinical trial indicated that amitifadine had statistically significant antidepressant effects and was well tolerated.[6]
Chemistry
Amitifadine is the (+)-enantiomer of DOV-216,303, and its (−)-enantiomer is DOV-102,677.
See also
References
- ↑ "Amitifadine". AdisInsight. Retrieved 26 February 2017.
- 1 2 3 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. PMID 12586204. doi:10.1016/S0014-2999(03)01310-4.
- ↑ http://adisinsight.springer.com/drugs/800017557
- ↑ http://euthymics.com/wp-content/uploads/2013/05/FINAL_Euthymics_TRIADE_Results_052913.pdf
- ↑ 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. PMID 22213370. doi:10.1002/syn.21531.
- ↑ 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. PMID 21925682. doi:10.1016/j.jpsychires.2011.09.003.