The milk: GABA-A, no ceiling, no analgesia
2,6-diisopropylphenol · C12H18O · MW 178.27 g/mol · CAS 2078-54-8 · Diprivan (1% lipid emulsion) · ChEMBL CHEMBL526
Propofol (Diprivan). An IV general anesthetic: a small phenol that positively modulates GABAA at transmembrane sites (not the extracellular benzodiazepine pocket). Unlike benzos, high-dose propofol can directly gate the channel — there is no tidy ceiling. It does not kill pain; it kills consciousness and, readily, ventilation. The white emulsion is a delivery system, not a kindness.
Propofol binds GABAA transmembrane subunit interfaces — overlapping in part with etomidate/barbiturate sites, distinct from the extracellular benzodiazepine site that diazepam #015 uses. PDB 6X3T is a genuine human α1β2γ2 structure with GABA plus propofol (Kim / Hibbs, Nature 2020). Positive modulation increases Cl− flux; at anesthetic concentrations it can open the channel with little GABA present.
Clinical consequences write themselves: no analgesia (pair with an opioid or local for surgery), dose-dependent apnea, vasodilation/hypotension, and a context-sensitive half-time that stays short for brief cases and lengthens with long ICU infusions. Propofol infusion syndrome (PRIS) is the metabolic disaster of high-dose, prolonged infusion — lactic acidosis, rhabdomyolysis, bradyarrhythmia.
Not the benzo pocket. 6X3T places propofol at β(+)/α(−) transmembrane interfaces. Flumazenil will not reverse it.
Low dose: more Cl⁻ per GABA pulse. Anesthetic dose: GABA-independent opening. That is the missing ceiling.
Unconscious is not painless. Intraoperative propofol still needs an analgesic plan.
Apnea, loss of airway reflexes, hypotension. This is why it is not a 'sleep shot' for the unmonitored.
1% propofol in soybean oil/egg lecithin. Pain on injection; rare egg/soy issues are overstated vs true allergy; hypertriglyceridemia on long infusion.
High-dose (>4 mg/kg/h) prolonged infusion: mitochondrial failure phenotype — acidosis, rhabdo, cardiac collapse. Stop the infusion; this is not 'more pressors.'
Onset ~30 s because it is a small lipophilic phenol. Offset after a bolus is redistribution, not metabolism. UGT1A9 glucuronidation and CYP2B6 hydroxylation clear it; long infusions fill the deep compartment and the wake-up lengthens.
Propofol has abuse liability among people with access (anesthesia staff) — a brief euphoric/unconscious interlude with a terrifying therapeutic index at home. Deaths in unmonitored settings are not mysterious; they are apnea without a bag-mask. This is closer to phenobarbital #039 (no ceiling) than to a Z-drug.
Propofol is tiny: two isopropyls and a phenol. It does not pay a large ΔS_conf penalty.
Binding energy is burial of hydrophobic surface in TMD interfaces plus a hydroxyl contact — a ligand
that fits like a wedge in a protein–lipid crevice. PDB 6X3T is the rare honest
anesthetic co-structure on this site. Shannon collapse is on the receptor (desensitized pore), not the ligand.
Airway, blood pressure, lipids, and the fact that flumazenil will not help.
| Target | Affinity | Rel. | Action |
|---|---|---|---|
|
GABAA TMD
β(+)/α(−) transmembrane PAM sites
|
anesthetic µM
PDB 6X3T ligand
|
PAM / gate | |
|
BZD site
extracellular α/γ
|
no
flumazenil-insensitive
|
No binding | |
|
Analgesic targets
opioid / NS
|
no
hypnosis ≠ analgesia
|
None | |
|
Direct gate
high concentration
|
yes
no ceiling like benzos
|
Anesthetic |