10. Competitive Antagonist vs. Negative Allosteric Modulator

A competitive antagonist directly and physically blocks access of the agonist to the receptor, whereas a negative allosteric modulator indirectly changes agonist binding by interacting at a secondary site on the receptor to diminish the ability of the agonist to bind to the primary site. While a competitive antagonist shifts the dose-response curve of an agonist indefinitely by increasing antagonist dose, the shift caused by an allosteric antagonist (negative allosteric modulator) reaches a limit. This limit is dictated by the cooperatively factor that represents the maximal magnitude of interaction between the allosteric and primary binding sites. This limit makes negative allosteric modulators safer and more amenable to producing fine tuning of receptor unction. This ceiling effect also ensures achieving the same response to a maximal dose of the antagonist regardless of different blood concentrations, e.g. due to differences in metabolism in one patient versus another. Another advantage of negative allosteric modulators is their higher organ selectivity as compared with competitive antagonists. This is because of uniqueness of the chemical nature of the allosteric site on the same receptor expressed in different tissues and organs. This is in contrast to the well conserved nature of the primary binding site. This results in better selectivity and less side effects of allosteric modulators.

This image above demonstrates the ceiling effect of a negative allosteric modulator/antagonist. The antagonist reduces the agonist response in a dose-dependent manner. However, this antagonism reaches a plateau even at higher doses. This is in contrast to complete inhibition of the agonist response by a competitive antagonist.

Why does this matter? There is need to reduce certain biological responses without completely shutting them down. For example, a person who has gastrointestinal spasms needs a modulator that returns the hyperactive state of gastric and intestinal muscles to normal, without causing complete paralysis of the gastrointestinal tract.

To summarize, ADVANTAGES of negative allosteric modulators over competitive antagonists include:

Ceiling Effect: can only inhibit agonist response to a certain point, protecting patient from excessive inhibition that could have serious consequences.
Fine-Tune ability: allosteric modulators have greater potential for receptor subtype selectivity than do competitive antagonists, and this minimizes side effects.