Receptor Occupancy
Receptor occupancy is the fraction of a receptor population bound by a ligand at a given concentration, set by affinity through the relation occupancy equals concentration divided by concentration plus Kd.
At equilibrium the fraction of receptors occupied by a reversible ligand follows from the law of mass action: occupancy equals free concentration divided by that concentration plus the dissociation constant. The arithmetic is unforgiving in a useful way. At a concentration equal to Kd, half the receptors are bound; nine times Kd gives 90 percent; ninety-nine times Kd gives 99 percent. Each extra decile of occupancy costs disproportionately more drug.
Occupancy and effect are rarely the same curve. Many tissues have receptor reserve — spare receptors — so the maximal response is reached with only a fraction of sites bound, pushing the functional EC50 well below the binding Kd. In central nervous system drug development, PET ligand studies made occupancy measurable in living subjects, and target occupancy windows derived that way, such as the roughly two-thirds to four-fifths striatal D2 occupancy associated with antipsychotic effect, now guide dose selection.
Occupancy is valuable because it links a plasma concentration to a target-level quantity comparable across compounds and species. It lets a dose be chosen from a mechanistic threshold rather than empirical titration, and identifies when a disappointing result reflects insufficient target engagement rather than a wrong target. It cannot tell you what the occupied receptor then does.
The mistake to watch for is treating an affinity figure as an occupancy figure. Occupancy depends on free concentration at the receptor, not total plasma concentration, so a heavily protein-bound or poorly distributed compound occupies far less than its Kd suggests. A spec sheet quoting sub-nanomolar affinity implies nothing if achievable concentrations at the target site are never established.