Definition
ChEBI: An N-arylpiperazine in which the aryl group is specified as 2-[(2,4-dimethylphenyl)sulfanyl]phenyl. Used (as its hydrobromide salt) for treatment of major depressive disorder.
Description
In September 2013, vortioxetine (also known as Lu AA21004) was approved in the United States for the treatment of major depressive disorder (MDD). Vortioxetine was discovered from a designed multiple ligand approach to identifying an antidepressant agent that combined SERT inhibition with 5-HT1A agonism to more rapidly desensitize 5-HT1A receptors and 5-HT3A antagonism to improve mood and cognitive function. Vortioxetine has a human SERT IC50=5.4 nM, an EC50=200 nM as a human 5-HT1A receptor agonist (efficacy=96%; Ki=39 nM), and an IC50=12 nM as a human 5-HT3A receptor antagonist (Ki=3.7 nM). It has weak inhibition of the dopamine and norepinephrine transporters, but high affinity for the human β1-noradrenergic receptor (Ki=46 nM), human 5-HT1B receptor (Ki=33 nM, partial agonist), and the human 5-HT-7 receptor (Ki=19 nM, antagonist).
Originator
Lundbeck (Denmark)
Uses
Vortioxetine can be used in biological study of effectiveness of long term vortioxetine treatment of patients with major depressive disorder.
Clinical Use
Antidepressant
Synthesis
The sequence involves iterative palladium-catalyzed carbon¨C
heteroatom bond formations, the first establishing the thioethereal
bond between commercially available thiol (213) and o-iodobromobenzene
(214) employing conditions described by Schopfer
and Schlapbach. Next, Buchwald¨CHartwig conditions were
employed to establish the piperazine linkage, and this was
followed by subjection to warm hydrobromic acid to furnish
vortioxetine hydrobromide (XXVI) in 75% yield across the entire
three-step sequence.
in vitro
vortioxetine (lu aa21004) was the lead compound, displaying high affinity for recombinant human 5-ht1a (ki = 15 nm), 5-ht1b (ki = 33 nm), 5-ht3a (ki = 3.7 nm), 5-ht7 (ki = 19 nm), and noradrenergic β1 (ki = 46 nm) receptors, and sert (ki = 1.6 nm). vortioxetine displayed antagonistic properties at 5-ht3a and 5-ht7 receptors, partial agonist properties at 5-ht1b receptors, agonistic properties at 5-ht1a receptors, and potent inhibition of sert [1].
in vivo
in conscious rats, vortioxetine significantly increased extracellular 5-ht levels in the brain after acute and 3 days of treatment. following the 3-day treatment (5 or 10 mg/kg/day) sert occupancies were only 43% and 57%, respectively [1].
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: avoid with linezolid; concentration
reduced by rifampicin - consider increasing
vortioxetine dose.
Antidepressants: possible increased risk of
convulsions with SSRIs and, tricyclics; avoid with
moclobemide; increased risk of hypertension and
CNS excitation with MAOIs - avoid.
Antiepileptics: concentration possibly reduced by
carbamazepine, fosphenytoin and phenytoin -
consider increasing vortioxetine dose.
Antimalarials: possible increased risk of convulsions
with mefloquine; avoid with artemether with
lumefantrine and artenimol with piperaquine.
Antipsychotics: possible increased risk of convulsions
with butyrophenones, phenothiazines and
thioxanthenes.
Dopaminergics: risk of CNS excitation and
hypertension with rasagiline and selegiline.
Metabolism
Vortioxetine is extensively metabolised in the liver, mainly
by oxidation catalysed by CYP2D6 and to a minor extent
CYP3A4/5 and CYP2C9, and subsequent glucuronic
acid conjugation. The major metabolite of vortioxetine is
pharmacologically inactive.
Approximately two thirds of the inactive vortioxetine
metabolites are excreted in the urine and approximately
one third in the faeces. Only negligible amounts of
vortioxetine are excreted in the faeces.
References
[1] bang-andersen b, ruhland t, j?rgensen m, smith g, frederiksen k, jensen kg, zhong h, nielsen sm, hogg s, m?rk a, stensb?l tb. discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (lu aa21004): a novel multimodal compound for the treatment of major depressive disorder. j med chem. 2011;54(9):3206-21.
[2] theunissen el, street d, h?jer am, vermeeren a, van oers a, ramaekers jg. a randomized trial on the acute and steady-state effects of a new antidepressant, vortioxetine (lu aa21004), on actual driving and cognition. clin pharmacol ther. 2013;93(6):493-501.
Figure 1 is a chemical reaction diagram for the synthesis of vortioxetine.
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