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Dopamine transporter (DAT)weak selective inhibitor

Norepinephrine transporterinhibits

Orexin / histamineraises

Dopamine transporter (DAT, SLC6A3)Inhibitor; blocks dopamine reuptake. The primary and only well-established direct molecular target.

Norepinephrine transporter (NET, SLC6A2)Negligible direct binding at attainable concentrations.

Serotonin transporter (SERT, SLC6A4)No meaningful interaction demonstrated.

Dopamine D2/D3 receptorsIndirect. Apparent occupancy changes because synaptic dopamine rises, not because modafinil binds the receptor.

Dopamine D1 receptorDownstream mediator of behavioural effect, not a binding site.

Orexin/hypocretin neurons (perifornical hypothalamus)Indirect circuit activation; not required for wake promotion.

Histaminergic tuberomammillary nucleus (TMN) neuronsIndirect circuit activation.

Mesencephalic dopamine neurons (VTA and substantia nigra pars compacta)Required downstream circuit for arousal.

Wakefulnesspromotes

Dopamine transporter (DAT)weak inhibitor

Histamine / orexinraises

Dopamine transporter (DAT, SLC6A3)Inhibits dopamine reuptake by binding the central S1 substrate site; it is not a releasing agent and is described as an atypical DAT inhibitor because it favours a more occluded, inward-facing transporter conformation than cocaine does. ChEMBL and the FDA label list DAT inhibition as the only curated mechanism of action.

Norepinephrine transporter (NET, SLC6A2)Essentially inactive; no meaningful inhibition at concentrations reachable with human dosing

Serotonin transporter (SERT, SLC6A4)Essentially inactive; no meaningful inhibition at concentrations reachable with human dosing

Dopamine D2 receptor (DRD2)No direct binding at relevant concentrations. D2 autoreceptor effects seen in brain slice electrophysiology are secondary to raised extracellular dopamine, not to receptor binding.

Dopamine D3 receptor (DRD3)Negligible direct binding

Sigma-1 receptor (SIGMAR1)No meaningful binding

Brainstem and hypothalamic arousal nuclei (tuberomammillary nucleus, locus coeruleus, dorsal raphe, pedunculopontine and laterodorsal tegmentum)Indirect downstream activation only; no binding site has been identified for armodafinil at any of these nuclei

CYP3A4/5 (induction) and CYP2C19 (inhibition)Moderate inducer of CYP3A4/5 and moderate inhibitor of CYP2C19; also a CYP3A4/5 substrate for sulfone formation, while amide hydrolysis is the main clearance route. This is the pharmacokinetic basis of the label's contraceptive failure warning.