Description
Atomoxetine is the first non-stimulant marketed for the treatment of attention deficit
hyperactivity disorder (ADHD). It is the R-stereoisomer of the racemate tomoxetine and
is a selective and potent norepinephrine uptake inhibitor (K
i=0.7–1.9 nM) that is
devoid of binding to monoamine receptor. It also has little effect on dopamine and
serotonin reuptake or acetylcholine, H1 histamine, alpha1 or alpha1-adrenergic or
dopamine receptors. It is prepared from racemic 1-phenylbut-3-en-1-ol via a selective
enzymatic acylation leaving the desired S-stereoisomer as the alcohol. This alcohol is
converted via a Mitsunobu reaction with ortho-cresol to the corresponding ether with
isomeric R-configuration. Ozonolysis and reduction steps provided the terminal alcohol
that is mesylated and displaced with methylamine. Its selectivity for norepinephrine
relative to dopamine inhibition was demonstrated in vivo preclinically. In a two-lever
(two condition) discriminative stimulus effect study in squirrel monkeys, tomoxetine
and other norepinephrine uptake inhibitors substituted for cocaine under low-dose
training conditions, whereas dopamine uptake inhibitors substituted for cocaine in both
low and high-dose conditions. In clinical ADHD studies in adolescents, it was
significantly different from placebo in 1.2 and 1.8 mpk/day dosing. In the clinical study
in adults using the CAARS scale a 95 mg/day dose provided greater than 30%
improvement in total scores. Atomoxetine is about 63% orally bioavailable, is highly
protein bound (98%, primarily to albumin) and has a half-life of about 5.2 h. It is
metabolized by CYP2D6 resulting in differential clearance for poor metabolizers (halflife
of 19 h with a 10 times higher AUC) relative to extensive metabolizers. The total
daily dose for children, adolescents and adults is a maximum of 100 mg/day. Common
side effects in children and adults include nausea, decreased appetite, and dizziness.
Adults may also have insomnia.
Description
Atomoxetine is a selective norepinephrine reuptake inhibitor with K
i values of 5, 77, and 1,451 nM for norepinephrine, serotonin, and dopamine transporters, respectively. It is selective over the choline, GABA, and adenosine transporters, and a number of neurotransmitter receptors, ion channels, second messengers, and brain/gut peptides. In the rat prefrontal cortex (PFC), it increases extracellular norepinephrine and dopamine by 3-fold and increases Fos expression. Atomoxetine (0.1, 0.5, and 1 mg/kg) reduces premature responding, a measure of impulsivity, by rats in the 5-choice serial reaction time test (5CSRTT) in a dose-dependent manner. It also has neuroprotective effects when administered prior to ischemic damage in a gerbil model of transient cerebral ischemia. Formulations containing atomoxetine have been used in the treatment of attention-deficit hyperactivity disorder (ADHD) in children, adolescents, and adults.
Chemical Properties
White Solid
Originator
Eli Lilly & Co (US)
Uses
Psychotherapeutic, Anti Depressant
Uses
A Norepinephrine reuptake inhibitor
Uses
(
R)-Tomoxetine hydrochloride has been used as a noradrenaline reuptake inhibitor:
- to study the role of L-threo-3,4-dihydroxyphenylserine (L-DOPS) in the pathogenesis of Alzheimer′s disease in mice
- to study its effects on set shifting in rats
- to study its effects on rat brain as a result of its long-term use
Uses
These Secondary Standards are qualified as Certified Reference Materials. These are suitable for use in several analytical applications including but not limited to pharma release testing, pharma method development for qualitative and quantitative analyses, food and beverage quality control testing, and other calibration requirements.
Atomoxetine hydrochloride may be used as a pharmaceutical reference standard for the determination of atomoxetine hydrochloride in pharmaceutical formulations by spectrophotometric method.
Definition
ChEBI: The hydrochloride salt of atomoxetine.
brand name
Strattera
(Lilly).
General Description
Atomoxetine hydrochloride is a nonstimulant used in the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children and adults.
Biological Activity
Potent and selective noradrenalin re-uptake inhibitor (K i values are 5, 77 and 1451 nM for inhibition of radioligand binding to human NET, SERT and DAT respectively). Displays minimal affinity for a range of other neurotransmitter receptors and transporters (K i > 1 μ M). Antidepressant.
Biochem/physiol Actions
Norepinephrine uptake blocker.
Synthesis
The 3-aryloxy substituent
was introduced utilizing a chiral alcohol by either the
Mitsunobu reaction or by nucleophilic aromatic
displacement. Because of the expense and difficulty of the
Mitsunobu reaction on large scale, the commercial process
adopts the nucleophilic aromatic substitution method. 3-
Chloropropiophenone (37) was asymmetrically reduced with
borane and catalytic amount of (S)-oxazaborolidine (8) in
THF at 0??C to give chiral alcohol 38 in 99% yield and 94% e.e. The chiral alcohol was further purified by recrystallization
to greater than 99% e.e.. Subsequent treatment
of chloride 38 with excess dimethylamine (40% in water) in
ethanol gave dimethylamine alcohol 39 in 90% yield.
Alcohol 39 was then subjected to nucleophilic aromatic
displacement in the presence of NaH in DMSO with 1-
fluoro-2-(t-butylimino)benzene (41), which was prepared in
high yield from 2-fluorobenzaldehyde (40). The
displacement product 42 was obtained in 98% yield, and the
imine 42 was subsequently hydrolyzed with acetic acid in
water at low temperature to give the corresponding aldehyde
43 in 96% yield. Sodium borohydride was employed to
reduce aldehyde 43 to alcohol in cold methanol and the
intermediate alcohol was converted to chloride 44 with
thionyl chloride. Chloride 44 was then reduced with zinc
metal under acidic conditions to give methyl adduct 45 in
95% yield and 94% e.e. Finally, phenyl chloroformate and
triethylamine was used to transform dimethylamine 45 to
monomethyl amine, which was subsequently treated with
HCl in EtOAc under reflux to give atomoxetin
hydrochloride (IV) in 98% yield and 99% e.e. from 45.
