Pharmacodynamics +<unk>  activity profile Site Potency Type Species Refs 1.8–2.6 μM4.8 μM6.4 μM4.0 μM KiKiIC50aIC50a HumanRatHumanRat >10 μM>92 μM35.6 μM136 μM KiKiIC50aIC50a HumanRatHumanRat >10 μM46.6 μM>500 μM>50 μM KiKiIC50aIC50a HumanRatHumanRat D2 >10 μM16 nMb120 nMb KiKiEC50a HumanRatRat Footnotes: a = Functional activity, not binding inhibition. b = Armodafinil at D2High. Notes: No activity at a variety of other assessed targets. Mechanism of action the precise therapeutic mechanism of action of<unk>  for narcolepsy and sleep-wake disorders remains unknown.<unk>  acts as an atypical, selective, and weak dopamine reuptake inhibitor and indirectly activates the release of orexin neuropeptides and histamine from the lateral hypothalamus and tuberomammillary nucleus, respectively all of which may contribute to heightened arousal. Dopamine reuptake inhibitor Research found that<unk>  elevates dopamine levels in the hypothalamus in animals. The locus of the monoamine action of<unk>  was also the target of studies, with effects identified on dopamine in the striatum and, in particular, nucleus accumbens, norepinephrine in the hypothalamus and ventrolateral preoptic nucleus, and serotonin in the amygdala and frontal cortex.<unk>  was screened at a large panel of receptors and transporters in an attempt to elucidate its pharmacology. Of the sites tested, it was found to significantly affect only the dopamine transporter (DAT), acting as a dopamine reuptake inhibitor (DRI) with an IC50 value of 4 μM. Subsequently, it was determined that<unk>  binds to the same site on the DAT as cocaine, but in a different manner. In accordance,<unk>  increases locomotor activity and extracellular dopamine concentrations in animals in a manner similar to the selective DRI vanoxerine (GBR-12909), and also inhibits methamphetamine-induced dopamine release (a common property of DRIs, since DAT transport facilitates methamphetamine's access to its intracellular targets). As such,<unk>  is an exceptionally weak, but apparently very selective, DAT inhibitor". In addition to animal research, a human positron emission tomography (PET) imaging study found that 200 mg and 300 mg doses of<unk>  resulted in DAT occupancy of 51.4% and 56.9%, respectively, which was described as "close to that of methylphenidate". Another human PET imaging study similarly found that<unk>  occupied the DAT and also determined that it significantly elevated extracellular levels of dopamine in the brain, including in the nucleus accumbens.<unk>  has been described as an "atypical" DAT inhibitor, and shows a profile of effects that is very different from those of other dopaminergic stimulants. For instance,<unk>  produces wakefulness reportedly without the need for compensatory sleep, and shows relatively low, if any, potential for abuse. Aside from<unk> , examples of other atypical DAT inhibitors include vanoxerine and benztropine, which have a relatively low abuse potential similar to<unk> . These drugs appear to interact molecularly with the DAT in a distinct way relative to "conventional" DAT blockers such as cocaine and methylphenidate. Analogues of<unk>  with<unk> -like versus cocaine-like dopamine reuptake inhibition and effects have been synthesized. Dopamine transporter-independent actions Against the hypothesis that<unk>  exerts its effects by acting as a DRI, tyrosine hydroxylase inhibitors (which deplete dopamine) fail to block the effects of<unk>  in animals. In addition,<unk>  fails to reverse reserpine-induced akinesia, whereas dextroamphetamine, a dopamine releasing agent (DRA), is able to do so. Moreover, one of the first published structure–activity relationship studies of<unk>  found in 2012 that DAT inhibition did not correlate with wakefulness-promoting effects in animals among<unk>  analogues. Additionally, a variety of analogues without any significant inhibition of the DAT still produced wakefulness-promoting effects. Furthermore, "the neurochemical effects of<unk>  and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory". Another study found that<unk> -induced increased locomotor activity in animals was dependent on histamine release and could be abolished by depletion of neuronal histamine, whereas those of methylphenidate were not and could not be. Taken together, although it is established that<unk>  is a clinically significant DRI, its full pharmacology remains unclear and may be more complex than this single property—as it may also include DAT-independent actions. One such action may be activation of the orexin system. In any case, there is nonetheless a good deal of evidence to indicate that<unk>  is producing at least a portion of its wakefulness-promoting effects by acting as a DRI, or at least via activation of the dopaminergic system. In support of<unk>  acting as a dopaminergic agent, its wakefulness-promoting effects are abolished in DAT knockout mice (although DAT knockout mice show D1 and D2 receptor and norepinephrine compensatory abnormalities that might confound this finding), reduced by both D1 and D2 receptor antagonists (although conflicting reports exist), and completely blocked by simultaneous inactivation of both D1 and D2 receptors. In accordance,<unk>  shows full stimulus generalization to other DAT inhibitors including cocaine, methylphenidate, and vanoxerine, and discrimination is blocked by administration of both ecopipam (SCH-39166), a D1 receptor antagonist, and haloperidol, a D2 receptor antagonist. Partial substitution was seen with the DRA dextroamphetamine and the D2 receptor agonist PNU-91356A, as well as with nicotine (which indirectly elevates dopamine levels through activation of nicotinic acetylcholine receptors).<unk>  may possess yet an additional mechanism of action. Both<unk>  and its metabolite,<unk>  sulfone, possess anticonvulsant properties in animals, and<unk>  sulfone is nearly as potent as<unk>  in producing this effect. However,<unk>  sulfone lacks any wakefulness-promoting effects in animals, indicating that a distinct mechanism may be at play in the anticonvulsant effects of both compounds. Dopamine D2 receptor partial agonist Armodafinil, the (R)-enantiomer of<unk> , was also subsequently found to act as a D2High receptor partial agonist, with a Ki of 16 nM, an intrinsic activity of 48%, and an EC50 of 120 nM, in rat striatal tissue. Esmodafinil, the (S)-enantiomer of<unk> , is inactive with respect to the D2 receptor.<unk>  has been found to directly inhibit the firing of midbrain dopaminergic neurons in the ventral tegmental area and substantia nigra of rats via activation of D2 receptors. However,<unk>  has also been reported not to interact with the human D2 receptor (Ki = >10 μM). Other actions An in vitro study predicts that<unk>  may induce the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as may inhibit CYP2C9 and CYP2C19. It may also induce P-glycoprotein, which may affect drugs transported by P-glycoprotein, such as digoxin. Pharmacokinetics The bioavailability of<unk>  is greater than 80% of the administered dose. Cmax (peak levels) occurs approximately 2 to 3 hours after administration. Food slows absorption, but does not affect the total AUC. In vitro measurements indicate that 60% of<unk>  is bound to plasma proteins at clinical concentrations of the drug. This percentage changes very little when the concentration of<unk>  is varied. The two major circulating metabolites of<unk>  are<unk>  acid (CRL-40467) and<unk>  sulfone (CRL-41056). Both of these metabolites have been described as inactive, and neither appear to contribute to the wakefulness-promoting effects of<unk> . However,<unk>  sulfone does appear to possess anticonvulsant effects, a property that it shares with<unk> . Elimination half-life is generally in the range of 10 to 12 hours, subject to differences in CYP genotypes, liver function and renal function. It is metabolized in the liver, and its inactive metabolite is excreted in the urine. Urinary excretion of the unchanged drug ranges from 0% to as high as 18.7%, depending on various factors.
Modafinil
Armodafinil
Methylphenidate
Adrafinil
Dexmethylphenidate
Ethylphenidate
Dimethazan
Fluparoxan