Wake without the reverse transport
2-[(diphenylmethyl)sulfinyl]acetamide · C15H15NO2S · MW 273.35 g/mol · CAS 68693-11-8 · Provigil · racemate; armodafinil is the R-enantiomer · ChEMBL CHEMBL1373
Modafinil (Provigil). A wakefulness-promoting atypical DAT inhibitor — it occupies the dopamine transporter, but it is not a substrate-releaser and does not run DAT in reverse the way amphetamine does. Therapeutic DAT occupancy is modest (~50%), which is why the subjective profile is "alert" more than "euphoric" at prescribed doses. FDA: narcolepsy, obstructive sleep apnea residual sleepiness, shift-work disorder.
Modafinil binds the dopamine transporter and raises extracellular dopamine, but binding kinetics and conformational preference differ from cocaine or methylphenidate. It is a weak-to-moderate affinity inhibitor (DAT IC50 / Ki typically high-nM to low-µM depending on assay), with negligible substrate-releaser activity. TAAR1 is not the story. Histaminergic and orexinergic wake circuitry is recruited secondarily via dopaminergic tone, not a direct H1 or OX2 agonism of clinical size.
That is why Schedule IV rather than II: lower reinforcing efficacy than classical stimulants in most models, though misuse exists (students, military, shift work). Armodafinil (Nuvigil) is the longer-lived R-enantiomer; the S-enantiomer clears faster. Rare but real: Stevens–Johnson / TEN and psychiatric adverse effects.
Occupies DAT S1 without the reverse-transport signature of amphetamine. Therapeutic occupancy ~50% — enough to promote wake, usually not enough to feel like cocaine.
No VMAT2 collapse, no TAAR1-driven DAT phosphorylation cascade. Mechanistically closer to a weak methylphenidate than to Adderall.
Dopamine in the nucleus accumbens and hypothalamus; downstream histamine/orexin recruitment. Direct orexin agonism is not the approved mechanism.
Much weaker at NET/SERT than at DAT. Not an SNRI in clinical clothing.
Amide hydrolysis + CYP3A4. Induces CYP3A4 modestly (can lower steroidal contraceptives — backup contraception is on the label).
Rare SJS/TEN/DRESS. Rash + fever + mucosal lesions = stop and emergency care, not a 'modafinil allergy' to push through.
Tmax ~2–4 h, t½ ~12–15 h (longer for armodafinil). Hepatic amide hydrolysis and CYP3A4; renal excretion of metabolites.
Modafinil will not protect you from sleep debt — it will mask it. Headache, anxiety, insomnia, and irritability are common. Psychiatric decompensation (mania, psychosis) is uncommon but documented. The contraceptive interaction is under-taught. Compared with methylphenidate #023 it is less of a classical DAT/NET blocker and less cardiovascularly punchy at labeled doses, but it is still a dopaminergic stimulant.
PDB 4XP4 shows cocaine occupying dDAT S1 — the same central site methylphenidate and (by homology) modafinil use. No modafinil co-crystal exists; occupancy data say the pose is real and the residence is shorter/weaker than cocaine. In FlexAIDΔS language the Shannon collapse of the S1 water network is incomplete relative to a high-affinity blocker, which is a thermodynamic reading of "atypical."
Schedule IV is not a vitamin. Rash, psychiatry, and contraception are the under-discussed harms.
| Target | Affinity | Rel. | Action |
|---|---|---|---|
|
DAT
dopamine transporter
|
IC50 ~µM / occupancy ~50%
atypical; assay-dependent
|
Inhibitor | |
|
NET
norepinephrine transporter
|
much weaker
not the clinical target
|
Weak | |
|
SERT
serotonin transporter
|
negligible at Rx
not an SSRI
|
Negligible | |
|
TAAR1 / VMAT2
releaser machinery
|
no
not amphetamine
|
Inactive |