Can a high concentration of agonist overcome the effect of a noncompetitive antagonist?

• A. No; noncompetitive antagonists reduce maximal response and cannot be overcome by increasing agonist.
• B. Yes; by simply adding more agonist you can achieve full response.
• C. Only at very high temperatures.
• D. Only in the presence of inverse agonists.

Answer: (A)

The key idea is that noncompetitive antagonists lower the maximum effect an agonist can produce, and this cannot be overcome simply by adding more agonist. They do not block by competing for the same binding site; instead they bind to the receptor in a way that either permanently disables it or changes its shape (allosteric effect) so the receptor signaling is impaired even when the receptor is occupied by agonist. Because a portion of receptors become or behave as nonfunctional, the system’s ceiling for response drops, no matter how much agonist you add. This is different from competitive antagonists, where enough extra agonist can outcompete the antagonist at the binding site and restore the maximum response.