Negative allosteric modulation

In biochemistry and pharmacology, an allosteric modulator (allo- from the Greek meaning "other") is a substance which indirectly influences (modulates) the effects of a primary ligand that directly activates or deactivates the function of a target protein. Targets may be metabotropic, ionotropic and nuclear receptors, enzymes and transporters. Allosteric modulators bind to a site distinct from that of the orthosteric binding site. They stabilize a conformation of the protein structure that affects either the binding or the efficacy of the primary ligand. Pure modulators have no direct effect on the function of the protein target. The modulatory properties are interdependent with the ternary complex consisting of the target protein, the primary ligand and the modulator.

Positive allosteric modulators (PAMs), also known as allosteric enhancers or potentiators, induce an amplification of the effect of the primary ligand. Most benzodiazepines act as PAMs at the GABA_A receptor.

Negative allosteric modulators (NAMs) reduce the effect of the primary ligand. Ro15-4513 is a NAM at the α1β2γ2 GABA_A receptor.

Silent allosteric modulators (SAMs), also called neutral or null modulators, occupy the allosteric binding site and behave functionally neutral. Flumazenil can be regarded as such an example.

The modulatory activity can be first-order, second-order, or both. Second-order modulators alter the modulatory activity of first-order modulators, whereas first-order modulators do not alter the activity of other allosteric modulators.(−)‐Epigallocatechin‐3‐gallate is one such example of a second-order modulator at GABA_A receptors.

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