Amphetamine with a lysine padlock
(2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide (lisdexamfetamine) → d-amphetamine payload · C15H25N3O · MW 263.38 g/mol (free base) · CAS 608137-32-2 · Vyvanse · ChEMBL CHEMBL1201747
Lisdexamfetamine (Vyvanse). A covalent L-lysine–d-amphetamine conjugate. It is inactive at DAT until red-cell aminopeptidases clip the lysine, releasing d-amphetamine (#006). The hydrolysis is rate-limited, which is the entire formulation trick: you cannot insufflate or inject your way around first-pass the way you can with instant-release amphetamine salts. Once the padlock opens, the pharmacology is amphetamine's.
Lisdexamfetamine does not bind DAT, NET, or TAAR1 at therapeutic concentrations. The amide between L-lysine and the amphetamine nitrogen is a pharmacological off-switch. Red-blood-cell aminopeptidase / hydrolase activity (not a CYP) hydrolyzes that amide and liberates d-amphetamine plus free lysine. From that moment the mechanism is identical to #006: DAT/NET substrate entry, vesicular depletion via VMAT2, reverse transport (efflux), and TAAR1 negative feedback.
The clinical point of the conjugate is pharmacokinetic, not pharmacodynamic. Hydrolysis has a ceiling set by red-cell enzyme capacity, so plasma d-amphetamine rises more slowly and more linearly with dose than instant-release mixed amphetamine salts. That blunts the rush from insufflation or IV use — the conjugate still has to be hydrolyzed — which is why it was developed as an abuse-deterrent ADHD product, not a new transporter ligand.
The lysine conjugate has negligible DAT/NET affinity. Swallowing, snorting, or injecting LDX does not put a releaser on the transporter until hydrolysis happens.
Rate-limited cleavage by red-cell aminopeptidases. This is why the conversion is not CYP2D6-gated (unlike many other psychiatric prodrugs) and why food has little effect on total exposure.
The payload is a substrate-releaser: it rides DAT/NET inward and reverses flux. DAT dopamine-release EC50 is in the high-nM to low-µM range for d-amphetamine (see #006).
Same downstream machinery as amphetamine: vesicular uncoupling and TAAR1 phosphorylation that internalizes DAT as a brake.
Insufflation/IV bypass of first-pass does not skip hydrolysis. Peak d-amphetamine is delayed versus instant-release salts — lower likeability in human abuse-liability studies, not zero.
FDA: ADHD (children and adults) and moderate-to-severe binge-eating disorder. Same cardiovascular and psychiatric stimulant warnings as other amphetamines.
Oral bioavailability of the conjugate is high; the slow step is hydrolysis. Parent LDX half-life is under an hour; d-amphetamine then tracks a ~10–13 h terminal half-life, similar to dosed amphetamine. Tmax of the payload is ~3.5–4.5 h — later than IR amphetamine — which is the clinical smoothness.
Once hydrolyzed, lisdexamfetamine is d-amphetamine. The differences that matter clinically — smoother onset, slightly lower likeability, once-daily coverage — are all in the input function, not a new receptor. CYP2D6 poor metabolizers still clear the payload more slowly; cardiovascular risk, insomnia, appetite suppression, and the rare psychosis signal are the amphetamine list. Do not stack with MAOIs. The "less abusable" claim is relative, not a safety guarantee: oral megadosing still delivers a full amphetamine exposure, just stretched over more hours.
Lisdexamfetamine itself is not a DAT ligand. In FlexAIDΔS terms the conjugate's binding entropy at the transporter is a non-event: the lysine tail wrecks the phenethylamine pharmacophore contacts that d-amphetamine uses in the S1 site (visualized here on PDB 7XNA, the amphetamine co-structure). The interesting −TΔS term is kinetic — the enzymatic barrier that meters appearance of the real ligand.
After hydrolysis, the payload is a small, rigid phenethylamine. As on the amphetamine page, DAT S1 binding is
dominated by ΔS_solvent (displacing ordered waters in the central site) rather than ligand
ΔS_conf. The lysine was a pharmacokinetic cage, not a docking feature.
Abuse-deterrent is not harmless. The payload is a Schedule II releaser with the usual stimulant toxicity.
| Target | Affinity | Rel. | Action |
|---|---|---|---|
|
DAT · d-AMP
dopamine transporter (payload)
|
release EC50 ~nM–µM
Rothman 2001 / ChEMBL
|
Substrate-releaser | |
|
NET · d-AMP
norepinephrine transporter
|
release EC50 ~nM
more potent at NET than DAT
|
Substrate-releaser | |
|
LDX parent
DAT / NET
|
negligible
inactive conjugate
|
Prodrug | |
|
TAAR1
trace-amine receptor 1
|
agonist (payload)
DAT internalization brake
|
Agonist |