Allosteric modulator
Neutral types don't affect agonist activity but can stop other modulators from binding to an allosteric site.
[2] Upon binding, modulators generally change the three-dimensional structure (i.e. conformation) of the receptor.
For all practical considerations, these combinations can be generalized only to 5 classes[4] and 1 neutral: Due to the variety of locations on receptors that can serve as sites for allosteric modulation, as well as the lack of regulatory sites surrounding them, allosteric modulators can act in a wide variety of mechanisms.
Barbiturates like phenobarbital bind β domains and increase the duration of each opening, but not the frequency.
With a higher probability of remaining in the active state, the receptor will bind agonist for longer.
AMPA receptors modulated by aniracetam and CX614 will deactivate slower, and facilitate more overall cation transport.
AMPA receptors are susceptible to desensitization via a disruption of a ligand-binding domain dimer interface.
Cyclothiazide has been shown to stabilize this interface and slow desensitization, and is therefore considered a positive allosteric modulator.
Lower pH increases the stability of the inactive state, and thereby decreases the sensitivity of the receptor.
[10] Modulators that increase only the affinity of partial and full agonists allow their efficacy maximum to be reached sooner at lower agonist concentrations – i.e. the slope and plateau of a dose-response curve shift to lower concentrations.
This can lower overdose risk relative to similarly acting orthosteric drugs.
It may also allow a strategy where doses large enough to saturate receptors can be taken safely to prolong the drug effects.
This is unlike orthosteric drugs, which tend to produce a less targeted effect within body on all of the receptors they can bind to.
[13] Allosteric modulation has demonstrated as beneficial to many conditions that have been previously difficult to control with other pharmaceuticals.
