[D]:
Aim: Investigate the activity (E/Emax) of a receptor-agonists complex (RD) in the presence of a non-competitive antagonist (A)!
Non competitive antagonism describes a situation where an antagonist (A) blocks the response not by competing with the agonist (D) for binding. Instead, the chain of events is blocked at some other point. A typical example is the inhibition of ligand gated ion channels (e.g. NMDA channels by ketamine or GABA channels picrotoxin). $${R + D} {\xrightleftharpoons[k_{-}]{k_{+}}} RD\;\;,\;\; {R + RD = 1}$$ $${C + A} {\xrightleftharpoons[k_{-}]{k_{+}}} CA\;\;,\;\; {C + CA = 1}$$ $${g = [RD]*[C]}$$
The first graph displays the kinetics of the formation of drug (D) receptor (R) complexes (RD, blue). The fraction of the receptor units that are not occupied by an antagonist (C) is shown in green and the effect (defined as ${E/E max = RD * C}$ ) is shown in red. The second graph illustrates the dependency of the steady state level of E/Emax on the drug concentration in the presence of a given concentration of a non competitive antagonist. Change the parameters of the reaction and evaluate the agonist-receptor interaction for a given antagonist concentration. Enter the parameters ([D] and [A]) and press "Apply". After having started the "experiment" only the concentration of the agonist [D] can be varied. The two curves illustrate the steady state levels of the formation of the agonist-receptor complexes in the absence (gray) and presence (red) of a non-competitive antagonist. See also Rang and Dale 5 th Edition, 2003 p. 9 ff.
µM
k-:
s-1
k+:
s-1
[A]:
µM
l-:
s-1
l+:
s-1
Non-competitive antagonism in pharmacodynamics refers to a type of drug interaction in which an antagonist does not compete with the agonist for the same receptor site, but rather reduces the overall efficacy of the agonist by altering the function of the receptor or the signaling pathway downstream from the receptor. Unlike competitive antagonists, non-competitive antagonists cannot be overcome by simply increasing the dose of the agonist. The effect of a non-competitive antagonist is not limited to blocking the agonist from binding to the receptor, but also reduces the ability of the receptor to respond to the agonist once it is bound.
The dose-response curve of the agonist in the presence of a non-competitive antagonist will show a reduction in Emax (the maximum effect of the agonist) but no change in EC50 (the concentration of the agonist required to produce half of the Emax). Non-competitive antagonists reduce the efficacy of the agonist by changing the way the receptor interacts with the agonist, making it less sensitive or responsive to the agonist.