In this simulation you can observe individual agonist and antagonist molecules competing for a limited number of receptors. Vary the agonist and antagonist concentrations and observe how receptor occupancy changes over time. Try increasing the agonist concentration while keeping the antagonist constant, then do the reverse; use high concentrations of both and see which ligand occupies more receptors; and hold the concentrations constant and watch whether the average occupancy approaches a stable value.
What are you seeing? This simulation displays microscopic binding events at a limited number of individual receptors, so binding and dissociation appear as random, discrete events rather than a smooth curve. At any moment the number of receptors occupied by agonist or antagonist may fluctuate considerably — these fluctuations are expected and reflect the stochastic nature of molecular interactions. As you observe the system for longer, the time-averaged receptor occupancy becomes more stable and provides a better estimate of the equilibrium occupancy. Because only a limited number of receptors are shown, you should not expect the smooth concentration–response curves seen in experiments with very large receptor populations; those macroscopic relationships emerge from the average behaviour of many individual interactions. Compare these microscopic observations with the concentration–response relationships explored in the following exercise.
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Competitive antagonism occurs when an antagonist and an agonist compete for the same, or overlapping, binding site on a receptor. An agonist binds to the receptor and activates it, producing a biological response. A competitive antagonist binds to the receptor but does not activate it. By occupying the binding site, the antagonist temporarily prevents the agonist from binding and therefore reduces the agonist’s effect.
The interaction can be represented schematically as:
Agonist + Receptor ⇌ Agonist–Receptor → Response
Antagonist + Receptor ⇌ Antagonist–Receptor → No activation
Because agonist and antagonist compete for the same population of receptors, their effects depend on their concentrations and binding affinities. An important feature of reversible competitive antagonism is that it is surmountable. Increasing the agonist concentration increases the probability that the agonist will occupy the receptor and can therefore overcome the effect of the antagonist. In a concentration–response experiment, a competitive antagonist typically shifts the agonist concentration–response curve to the right: a higher agonist concentration is required to produce the same response, while the maximum response can still be reached if sufficient agonist is present.
A classic example is atropine, which competitively blocks the binding of acetylcholine to muscarinic acetylcholine receptors. Competitive antagonism can also occur at ligand-gated ion channels — for example, competitive antagonists of nicotinic acetylcholine receptors prevent acetylcholine from binding and thereby reduce receptor activation and ion-channel opening.
Competitive versus non-competitive antagonism
Competitive antagonists compete directly with the agonist for receptor occupancy, so their effect can usually be overcome by increasing the agonist concentration. In non-competitive antagonism, inhibition cannot be fully overcome simply by adding more agonist. This may occur because the antagonist binds irreversibly to the agonist-binding site, or binds elsewhere on the receptor and alters its function. As a consequence, the maximum response to the agonist may be reduced.