Atomoxetine HCl

Atomoxetine HCl is a selective norepinephrine transporter inhibitor (Ki= 5 nM)

Norepinephrine transporter is a multi-pass membrane protein that is essential for norepinephrine reuptake into presynaptic nerve terminals and regulates norepinephrine homeostasis.

Atomoxetine blocked coupling of radioligands to clonal cell lines that transfected with human norepinephrine transporter, serotonin and dopamine transporters with Ki= 5, 77 and 1451 nM respectively. [1]

In microdialysis studies in rat, atomoxetine increases extracellular levels of norepinephrine transporter in prefrontal cortex 3-fold without altering 5-HTEX levels. Atomoxetine also increases DAEX concentrations in PFC 3-fold without altering DAEX in striatum or nucleus accumbens. Comparing with methylphenidate, atomoxetine do not increase DA in striatum or nucleus accumbens, indicating it would not have motoric or drug abuse liabilities. [1]

Reference:
Bymaster FP, Katner JS, Nelson DL et al.  Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002 Nov;27(5):699-711.

Structural determination of the stable and meta-stable forms of atomoxetine HCl using single crystal and powder X-ray diffraction methods.[Pubmed:16732589]

J Pharm Sci. 2006 Aug;95(8):1677-83.

Stratteratrade mark is the first FDA-approved nonstimulant medication for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children, adolescents, and adults. Two polymorphic forms and an amorphous form of the active pharmaceutical ingredient, Atomoxetine HCl, were discovered during drug development. The thermodynamically stable polymorphic form was selected for the commercial product. The stable form readily grows as crystals suitable for single crystal diffraction. The meta-stable crystal form is isolated by rapid crystallization, providing crystals that are too small for routine single crystal methods; consequently its structure was determined by X-ray powder diffraction.

Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder.[Pubmed:12431845]

Neuropsychopharmacology. 2002 Nov;27(5):699-711.

The selective norepinephrine (NE) transporter inhibitor atomoxetine (formerly called tomoxetine or LY139603) has been shown to alleviate symptoms in Attention Deficit/Hyperactivity Disorder (ADHD). We investigated the mechanism of action of atomoxetine in ADHD by evaluating the interaction of atomoxetine with monoamine transporters, the effects on extracellular levels of monoamines, and the expression of the neuronal activity marker Fos in brain regions. Atomoxetine inhibited binding of radioligands to clonal cell lines transfected with human NE, serotonin (5-HT) and dopamine (DA) transporters with dissociation constants (K(i)) values of 5, 77 and 1451 nM, respectively, demonstrating selectivity for NE transporters. In microdialysis studies, atomoxetine increased extracellular (EX) levels of NE in prefrontal cortex (PFC) 3-fold, but did not alter 5-HT(EX) levels. Atomoxetine also increased DA(EX) concentrations in PFC 3-fold, but did not alter DA(EX) in striatum or nucleus accumbens. In contrast, the psychostimulant methylphenidate, which is used in ADHD therapy, increased NE(EX) and DA(EX) equally in PFC, but also increased DA(EX) in the striatum and nucleus accumbens to the same level. The expression of the neuronal activity marker Fos was increased 3.7-fold in PFC by atomoxetine administration, but was not increased in the striatum or nucleus accumbens, consistent with the regional distribution of increased DA(EX). We hypothesize that the atomoxetine-induced increase of catecholamines in PFC, a region involved in attention and memory, mediates the therapeutic effects of atomoxetine in ADHD. In contrast to methylphenidate, atomoxetine did not increase DA in striatum or nucleus accumbens, suggesting it would not have motoric or drug abuse liabilities.

A new inhibitor of norepinephrine uptake devoid of affinity for receptors in rat brain.[Pubmed:6123593]

J Pharmacol Exp Ther. 1982 Jul;222(1):61-5.

LY135252, (+/-)-N-methyl-gamma-(2-methylphenoxy) phenylpropylamine hydrochloride, is a competitive inhibitor of norepinephrine uptake in synaptosomes of rat hypothalamus. The resolved optical (-)-isomer, LY139603, is 2 and 9 times more effective than the racemate and the (+)-isomer, LY139602, with inhibitor constants (Ki) of 1.9, 3.4 and 16.8 nM, respectively. All three compounds are relatively weak in the inhibition of dopamine and serotonin uptake, with Ki values at least two orders of magnitude greater. The racemate and the two optical isomers in vivo are potent inhibitors of norepinephrine uptake with relative effectiveness being parallel with their K1 values. The most potent and long-acting compound was the (-)-isomer, LY139603, which inhibited norepinephrine uptake ex vivo with an ED50 value of 2.2 mg/kg i.p, and a half-life of 6.4 hr. In comparison with the tricyclic antidepressants desipramine and imipramine, LY139603 is a relatively weak ligand for alpha-1, alpha-2, and beta adrenergic receptors, acetylcholine-muscarinic receptors, histaminergic H1 receptors and the receptors of gamma-aminobutyric acid and benzodiazepines. Thus, LY139603 is a remarkably specific inhibitor of norepinephrine uptake. Its potential as an antidepressant is discussed.

Atomoxetine hydrochloride is a potent and selective noradrenalin re-uptake inhibitor (Ki values are 5, 77 and 1451 nM for inhibition of radioligand binding to human NET, SERT and DAT respectively).

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