Receptor residence time
pharmacologyHow long a molecule stays bound to its receptor before dissociating, a kinetic property distinct from how tightly it binds at equilibrium. Slow dissociation can extend a substance's effect beyond what its concentration in blood would predict, though for most compounds here the value has never been measured.
Receptor residence time is a measure of how long, on average, a drug molecule stays attached to its target receptor before releasing and drifting away. It is a kinetic property — describing the speed of dissociation — distinct from affinity, which is a thermodynamic measure of how tightly the molecule binds at equilibrium.
The practical consequence is that a drug's effect can outlast its concentration in blood. A molecule already docked at a receptor continues to act while the body clears the drug from circulation, and dissociation, not elimination, sets the clock on how long that effect lasts.
How it works · its role
Every binding event has two rates: association (the molecule arriving at the receptor) and dissociation (the molecule leaving). Equilibrium affinity reflects the ratio of these two rates — it does not reveal their individual speeds. Two drugs with identical affinity can differ by orders of magnitude in how quickly they depart the receptor.
Residence time is the inverse of the dissociation rate. A slow dissociation rate means a long residence time: the molecule clings to the receptor for seconds, minutes, or longer, depending on the drug-receptor pair. During that window, the receptor remains occupied and downstream signalling continues regardless of whether the drug is still detectable in plasma.
Relevance to substances & effects
The concept is most studied in the context of antipsychotic drugs acting on dopamine D2 receptors. The 'fast-off' hypothesis proposes that atypical antipsychotics such as clozapine dissociate from D2 receptors more quickly than older agents like haloperidol. Faster exit is thought to reduce extrapyramidal adverse effects by allowing naturally released dopamine to compete for receptor access in the brief windows between drug-occupancy episodes.
NMDA receptor antagonists illustrate a related principle: drugs that block the ion channel depend partly on how quickly they exit between channel openings. This property influences both the therapeutic window and the subjective character of the effect.
For most psychoactive substances, precise residence time values are unmeasured or available only from in vitro studies that may not translate directly to effects in the living brain. Where subjective effects outlast measured blood concentrations, slow dissociation is a plausible explanation — though it is rarely the only one, and the data to confirm it are seldom collected.
AI-generated · not yet verified by a human reviewer
Harm-reduction reference — not medical advice.