TMA-2
Targets in the model
11
each with a measured Kᵢ
A one-compartment model of what TMA-2 might do over time, at a dose and by a route you choose. The affinities driving the occupancy calculation are measured and this archive holds them; the pharmacokinetics are mostly estimated, and the table at the foot of the page says which is which. The measured dossier · method
The input
First-order gastrointestinal absorption with a rate constant giving a peak near one hour, and a bioavailability reduced by first-pass metabolism. Both are class placeholders; where a compound has a published oral F it overrides this. Bioavailability for this route is 0.3 and the absorption rate constant 1.2 h⁻¹, both properties of the route rather than of TMA-2.
Modelled concentration
3 h 36 min
One compartment with first-order absorption. It cannot show a distribution phase, so the first minutes after an intravenous dose are the least trustworthy part of the curve. Peak effect-site concentration is 19 nM.
Reported milestones
Model landmarks
These are not observations. Each one is a feature of the curve above, read off the figure and moving with it whenever you change a parameter.
Dose given0
The model starts here.
Peak plasma1 h 43 min
Modelled maximum of 64.2 nM total plasma concentration.
Peak effect site2 h 8 min
Modelled maximum of 18.9 nM at the effect site — the concentration the occupancy below is computed from.
Modelled receptor occupancy at 3 h 36 min
O = C/(C+Kᵢ) at the effect-site concentration above. The Kᵢ is measured and this archive holds it; the C is modelled. Equilibrium is assumed at every instant, with no receptor reserve, no active metabolite and no tolerance.
This archive holds no pChEMBL value for the pair, and holds one for others of this compound — so the absence is ChEMBL’s, not a gap in the harvest. ChEMBL withholds a pChEMBL where the activity is not a comparable, meaningful result: an inexact relation, an unrecognised type, or a screen the depositor marked inactive. The concentration is shown because it is what the archive holds, and it is ranked below everything vouched for because it is not evidence of binding. Ketamine against the APE1 endonuclease is the example that earned this footnote: ChEMBL records that screen as inactive, and read as an affinity it made a DNA-repair enzyme ketamine’s tightest binder by two orders of magnitude.
Modelled regional engagement
Occupancy at each target multiplied by that target’s transcript level in the region, summed. This product is the model speaking. A dossier’s Systems plate deliberately refuses to compute it, because there it would read as a finding; here it is an output with its assumptions on the page. Transcript is not receptor density, and a region shaded here is a region where the model says binding could occur, not one shown to be affected.
And nothing checks it. The concentration plot above carries reported milestones because human studies state times; this figure has no counterpart. The human imaging work this archive cites reports connectivity change across a cortical parcellation, which is a different quantity in a different set of regions — the atlas holds the cortex as one — so it can neither confirm nor contradict the shading here, and translating it onto these thirteen regions would assert a correspondence nobody has published.
Brain
Body
Shading is on a fixed scale — the strongest engagement reached anywhere during the whole run — so the figures dim as the compound clears instead of renormalising to whatever the current instant happens to hold. Outlines from the EMBL-EBI Anatomogram, the same plates the dossiers use.
Brain regions
- cerebral cortex
- midbrain
- basal ganglia
- hypothalamus
- amygdala
- hippocampal formation
- cerebellum
- spinal cord
- pituitary gland
- retina
Peripheral & autonomic
- liver
- small intestine
- pancreas
- lung
- spleen
- urinary bladder
- duodenum
- smooth muscle
- stomach 1
- salivary gland
- heart muscle
- colon
Parameters
The whole model is these five numbers plus the route. Each says whether anyone measured it for TMA-2. Edit any of them; nothing here is written back to the archive.
How long the plasma concentration takes to halve once absorption is over.
Median terminal half-life across the compounds here with a published one. Applied to TMA-2 because no value for it was found.
Apparent volume the dose would occupy at the plasma concentration. Large means the compound leaves the blood for tissue.
Median apparent volume across the compounds in this file with a published value. These are mostly lipophilic amines that distribute well beyond total body water (0.6 L/kg), so a value in the low single digits is the right order; a highly lipophilic cannabinoid is an order of magnitude higher and is given its own value. Applied to TMA-2 because no value for it was found.
The share of plasma drug not bound to protein. Only unbound drug crosses into the brain.
Plasma protein binding is unmeasured for most of this archive. 0.3 is unremarkable for a small lipophilic base; a strongly bound cannabinoid is nearer 0.03 and is set individually. Applied to TMA-2 because no value for it was found.
Unbound brain concentration divided by unbound plasma. Below 1 implies active efflux; 1 is passive equilibration.
Unbound brain concentration equal to unbound plasma — i.e. passive equilibration with no net transport. This is the least committal assumption available and it is certainly wrong in detail for any compound that is a P-glycoprotein substrate, where the true value is below 1. Applied to TMA-2 because no value for it was found.
How fast the receptor compartment follows plasma. Small values put the peak effect long after the peak concentration.
Effect-site equilibration half-time of about 14 minutes, chosen so that modelled occupancy lags plasma by roughly the delay between peak plasma and peak subjective effect reported for the compounds here that have both. Applied to TMA-2 because no value for it was found.