3 Clinical psychopharmacology3.3 Pharmacodynamics
3.3.1.5.2 Agonism, antagonism, partial and inverse agonism
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Written by Resident Doctor Committee · Published
Basic terms
Affinity describes how well a drug binds a receptor, and efficacy describes how well it activates the receptor once bound.
Intrinsic activity is efficacy on a scale where a full agonist is conventionally assigned 1.
Log concentration-response curves are usually sigmoid. EC50 is the concentration giving half the drug's own maximum, and Emax is that maximum response.
Potency also depends on receptor reserve, amplification and exposure, so EC50 differs from the dissociation constant (Kd).
Full agonists
A full agonist binds the endogenous transmitter's (orthosteric) site with maximal intrinsic activity and reproduces the transmitter's whole effect, giving the largest response the system can produce.
Being a full agonist says nothing about potency.
Methadone is a full agonist at the mu-opioid receptor, as are morphine and fentanyl. Respiratory depression keeps rising with dose, so overdose can kill.
Partial agonists
A partial agonist activates its receptor but gives only a submaximal response even at full occupancy. Its limit is efficacy, not affinity.
Where transmitter is scarce, a partial agonist adds signalling. Where a full agonist is present, it competes for the receptor and lowers the response.
A large receptor reserve can make a partial agonist look full.
Drug | Receptor action | Clinical consequence |
|---|---|---|
Aripiprazole | Partial agonist at D2, D3 and 5-HT1A; 5-HT2A antagonist | Stimulates D2 where dopamine is scarce, acts as a functional antagonist where it is high |
Brexpiprazole | Partial agonist at D2 and 5-HT1A | With low tuberoinfundibular dopamine tone, prolactin falls rather than rises, as with aripiprazole |
Cariprazine | D2 partial agonist | Differs from brexpiprazole in intrinsic activity and D3 affinity |
Buprenorphine | High-affinity, low-intrinsic-activity partial agonist at mu-opioid receptors | Precipitates withdrawal if given while heroin still occupies the receptors; its effect on breathing plateaus |
Varenicline | Partial agonist at alpha-4 beta-2 nicotinic receptors | Releases enough dopamine to ease craving and withdrawal while blunting the reward from smoking |
Buspirone | Azapirone partial agonist at serotonin (5-HT1A) receptors | Anxiolytic effect builds over weeks; no dependence or withdrawal |
Aripiprazole differs from most antipsychotics, such as haloperidol, which are D2 antagonists.
Buprenorphine's respiratory ceiling does not remove overdose risk. Its slow dissociation prolongs its action, so toxicity may need repeated naloxone or an infusion.
Mixed agonist-antagonists
A mixed agonist-antagonist is an agonist at one receptor and an antagonist at another: pentazocine activates kappa-opioid receptors and has antagonist activity at mu.
Antagonists
Type | How it acts | Effect on the curve | Examples |
|---|---|---|---|
Competitive | Competes with the agonist for one site; more agonist overcomes it | Parallel rightward shift, maximum intact | Atropine, hyoscine, naloxone at mu-opioid receptors, haloperidol at D2 |
Non-competitive | Allosteric inhibition, channel block or block of downstream signalling | Maximum falls; more agonist cannot fully restore it | Memantine, ketamine |
Irreversible | Binds covalently and removes receptors | Shifts right while spare receptors remain; maximum falls once reserve is exhausted | Phenoxybenzamine at alpha-adrenoceptors |
The dose ratio compares EC50 with and without the antagonist.
An irreversible antagonist acts longer than it stays in plasma and stops only when the cell makes new receptors. No amount of agonist reclaims the occupied receptors.
Disulfiram irreversibly inhibits the enzyme aldehyde dehydrogenase, so acetaldehyde builds up with alcohol. Activity returns only as new enzyme is made, so a reaction can follow drinking days after the last dose.
Memantine is strictly an uncompetitive N-methyl-D-aspartate (NMDA) antagonist. It enters the channel once glutamate has opened it and lodges near the magnesium site, as ketamine and phencyclidine do, never occupying the glutamate site.
Memantine unbinds fast, so normal synaptic signalling continues.
Inverse agonists
Constitutive activity is spontaneous receptor signalling with no agonist bound. Inverse agonism can be shown only where this activity is measurable.
An inverse agonist has negative efficacy: given alone, it lowers receptor activity below baseline and produces the opposite of a full agonist.
A neutral antagonist has no efficacy of its own, so given alone it leaves baseline unchanged.
Drug | Site | Effect |
|---|---|---|
Beta-carboline | Benzodiazepine site of the gamma-aminobutyric acid A (GABA-A) receptor | Reduces GABA's chloride current, causing anxiety and seizures where diazepam calms and protects |
Pimavanserin | 5-HT2A receptors, which signal spontaneously | Used for psychosis in Parkinson's disease |
Many antihistamines and beta-blockers show inverse agonism in assays, but its clinical significance varies.
Allosteric modulators
Allosteric modulators bind a site distinct from the endogenous ligand's and change the receptor's response to it without competing. They can alter affinity, efficacy or both.
A positive allosteric modulator enhances the response to the endogenous agonist without activating the receptor alone. A negative modulator reduces that response.
An allosteric agonist binds outside the transmitter site but activates the receptor directly.
Diazepam and other benzodiazepine-site ligands are positive allosteric modulators at the GABA-A receptor, enhancing GABA-driven channel opening.
Pure modulators preserve aspects of transmitter timing and often show a ceiling. Benzodiazepine overdose alone is rarely fatal, but combinations with other depressants are dangerous.
Barbiturates can open the channel directly at high concentrations.
Flumazenil is the antagonist at the benzodiazepine site. It occupies the site without activating it, so it blocks benzodiazepines, Z-drugs and inverse agonists, and it can precipitate seizures in dependence.