Partial agonists and buprenorphine
A partial agonist binds a receptor and activates it only partly, so its response has a ceiling below the maximum, however high the dose.
Remember
A partial agonist has intermediate efficacy: alone it acts as an agonist, but beside a full agonist (a drug that produces the maximum response the tissue can give) it lowers the total response, like an antagonist.
Memory aid
A dimmer switch: a full agonist can turn the light fully up, a partial agonist stops part of the way however hard you push, and an antagonist leaves the light off.
Picture a dimmer switch to remember that a partial agonist stops part of the way up, however hard you push.
Two properties describe how a drug acts at a receptor. Affinity is how tightly a drug binds. Efficacy is the size of the response a drug produces once it has bound. Efficacy runs from maximum for a full agonist, through intermediate for a partial agonist, to zero for an antagonist (a blocker that occupies the receptor without activating it).
A partial agonist can bind with high affinity, so poor binding is not what limits it. It activates the receptor, but only to a sub-maximal response, below the maximum even when every receptor is occupied. Adding more drug occupies more receptors but does not raise the response above that ceiling.
Alone, a partial agonist acts as an agonist. Beside a full agonist at a high dose, it competes for the same receptors, and each one it takes is activated less strongly, so the total response falls towards the partial agonist's own ceiling. In that situation it behaves like an antagonist.
Buprenorphine is the classic example. At the mu-opioid receptor it works as a partial agonist, and it is used in opioid substitution therapy (replacement treatment for opioid use disorder). It binds with high affinity but gives a sub-maximal response, which has two useful effects. It provides enough opioid effect to suppress withdrawal, and because its effect has a ceiling, respiratory depression (slowed, reduced breathing) is less likely in overdose than with a full agonist such as heroin.
The ceiling lowers but does not remove the overdose risk. Buprenorphine with other sedating drugs significantly raises the risk of a fatal overdose.
Key facts
- Affinity
- high affinity means tight binding and says nothing about whether the receptor is activated.
- Efficacy ladder
- maximum for a full agonist, intermediate for a partial agonist and zero for an antagonist.
- Dual behaviour
- an agonist by itself, but antagonist-like beside a full agonist.
- Ceiling
- a higher dose occupies more receptors, but it cannot lift the response above the partial agonist's own maximum.
- Potency versus efficacy
- low potency means more drug is needed, whereas efficacy sets the size of the maximum response.
- Buprenorphine
- at the mu-opioid receptor it works as a partial agonist that suppresses withdrawal and makes respiratory depression in overdose less likely than with a full agonist such as heroin.
Exam traps
- A partial agonist does not have high efficacy. Its efficacy is intermediate, so it stays below the response of a full agonist, and tight binding (high affinity) is a different property.
- A full agonist with low potency does not explain a lower maximum, because low potency means a higher dose is needed, yet the same maximum is still reached.
- A partial agonist's lower maximum is a limit of efficacy, not of loose binding. Buprenorphine binds with high affinity, so a higher dose does not lift it to the maximum of a full agonist.
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