[D]:
Aim: Analyse the receptor (R) occupancy by an agonist (D) in the presence of a given concentration of a competitive antagonist (A)!
Left graph — binding kinetics. The left graph shows how receptor occupancy develops over time. The formation of agonist–receptor complexes (RD, red) is shown together with the simultaneous formation of antagonist–receptor complexes (RA, blue). $${R + D} {\xrightleftharpoons[k_{-}]{k_{+}}} RD\;\;,\;\; {R + A} {\xrightleftharpoons[l_{-}]{l_{+}}} RA\;\;,\;\; {R + RD + RA =1}$$ Because agonist and antagonist compete for the same receptor population, an increase in antagonist binding reduces the number of receptors available for the agonist. Over time, association and dissociation approach a steady state. Observe how quickly the two complexes form and the steady-state level reached under different conditions.
Right graph — concentration dependence. The right graph shows the steady-state level of agonist–receptor complexes (RD) as a function of agonist concentration, for two cases: without antagonist (the reference curve) and with a fixed antagonist concentration. In the presence of a competitive antagonist the agonist curve shifts to the right, so a higher agonist concentration is required to achieve the same occupancy or response — yet at sufficiently high agonist concentrations the antagonist’s effect can be overcome and the same maximal level reached.
Try it yourself. Enter a given [D] and [A] and press Apply to start the experiment; then vary the agonist concentration while keeping the antagonist constant. Watch how increasing [D] raises agonist–receptor complex formation, how the antagonist reduces agonist binding at a given [D], and how increasing [D] can overcome this inhibition. Repeat with different antagonist concentrations: as [A] increases, progressively higher agonist concentrations are needed for the same response — a parallel rightward shift with increased EC50 and unchanged Emax.
µM
k-:
s-1
k+:
s-1
[A]:
µM
l-:
s-1
l+:
s-1
In competitive antagonism, an agonist and an antagonist compete reversibly for the same, or overlapping, binding site on a receptor. The agonist binds and activates the receptor, whereas the competitive antagonist binds without activating it; occupancy by the antagonist temporarily prevents the agonist from binding. Because the interaction is reversible, the antagonistic effect can be overcome by increasing the agonist concentration — at higher agonist concentrations, agonist molecules are increasingly able to compete successfully for receptor binding.
This produces a characteristic change in the agonist concentration–response curve:
- the curve shifts parallel to the right;
- a higher agonist concentration is required to produce the same response;
- the EC50 increases;
- the maximum response (Emax) remains unchanged.
Thus, a reversible competitive antagonist reduces the apparent potency of the agonist but does not reduce its maximal efficacy. The greater the antagonist concentration, the larger the rightward shift of the curve, while its slope and maximum remain essentially unchanged. This surmountable, parallel rightward shift is one of the defining features of reversible competitive antagonism.