Pharmacology
Inverse agonists and constitutive receptor activity
An inverse agonist is a drug that binds a receptor and lowers its signalling below the baseline (the resting level of signalling when nothing is bound to it).
Remember
Test the drug on its own: if signalling falls below the baseline, it is an inverse agonist, whereas a neutral antagonist (a drug that blocks an agonist yet leaves the baseline alone) does not lower it.
Some receptors are active even with nothing bound to them. They have constitutive activity: they give a low, steady signal with no ligand bound (a ligand is a molecule that binds the receptor). These receptors can flip spontaneously between an active form and an inactive form (these forms are called conformations), so at any moment a small fraction of them are active.
An agonist raises signalling above the baseline. A neutral antagonist sits on the receptor and blocks an agonist, but the baseline is unchanged. An inverse agonist binds the receptor and favours the inactive conformation, so fewer receptors are active and signalling falls below the resting level. That is the opposite effect to an agonist, and it is not the same as an antagonist.
Ask what the drug does when it is given alone. Drug X alone pushes the signal below baseline. Drug Y alone changes nothing, yet, given together with Drug X, it brings the signal back to baseline. Drug X is the inverse agonist. Drug Y sits on the receptor, has no activity of its own and blocks Drug X, so it is a neutral antagonist.
When a drug blunts the response to a full agonist (an agonist giving the largest response the system can produce), that alone does not identify the drug. An inverse agonist occupies the receptor, so it does this, but any antagonist could blunt an agonist.
The antihistamine cetirizine is a practical example, and it is now thought to be an inverse agonist rather than a simple antagonist.
Memory aid
an agonist turns the dial up, a neutral antagonist holds the dial still, and an inverse agonist turns the dial down
Picture the baseline signal as a dial and ask which way the drug moves it when given alone.
Key facts
- Constitutive activity
- some receptors signal at a baseline level when no ligand is bound.
- Inverse agonist
- binds the receptor and lowers signalling below the resting level by favouring the inactive conformation.
- Neutral antagonist
- blocks an agonist, yet the baseline signalling stays unchanged.
- Agonist
- raises signalling above the baseline.
- Deciding test
- the drug given alone lowers signalling below the baseline, which points to an inverse agonist.
- Blunted agonist response
- any antagonist can do this, so it does not identify the drug by itself.
- Clinical example
- cetirizine, an antihistamine, is now thought to be an inverse agonist, rather than a simple antagonist.
Exam traps
- A competitive antagonist (it sits at the agonist's own binding site yet gives no response of its own) does not fit, because given alone it leaves signalling at baseline.
- A partial agonist (an agonist with limited efficacy) can blunt a full agonist, but given alone it still raises signalling, so a fall below baseline is not its pattern.
- A non-competitive antagonist can reduce the effect of an agonist, for example by binding at a separate site, but on its own it does not push signalling under the resting baseline, so a fall below baseline is not what defines it.
- A full agonist switches the receptor on, giving the largest response, so signalling would rise above baseline, while an inverse agonist makes it fall.
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