Allosteric modulator
In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs.[1] The site that an allosteric modulator binds to (i.e., an allosteric site) is not the same one to which an endogenous agonist of the receptor would bind (i.e., an orthosteric site). Modulators and agonists can both be called receptor ligands.[2]
Allosteric modulators can be 1 of 3 types either: positive, negative or neutral. Positive types increase the response of the receptor by increasing the probability that an agonist will bind to a receptor (i.e. affinity), increasing its ability to activate the receptor (i.e. efficacy), or both. Negative types decrease the agonist affinity and/or efficacy. Neutral types don't affect agonist activity but can stop other modulators from binding to an allosteric site. Some modulators also work as allosteric agonists and yield an agonistic effect by themselves.[2]
The term "allosteric" derives from the Greek language. Allos means "other", and stereos, "solid" or "shape". This can be translated to "other shape", which indicates the conformational changes within receptors caused by the modulators through which the modulators affect the receptor function.[3]
A modulator can have 3 effects within a receptor. One is its capability or incapability to activate a receptor (2 possibilities). The other two are agonist affinity and efficacy. They may be increased, lowered or left unaffected (3 and 3 possibilities). This yields 17 possible modulator combinations.[4] There are 18 (=2*3*3) if neutral modulator type is also included.
For all practical considerations, these combinations can be generalized only to 5 classes[4] and 1 neutral:
PAMs shift initial agonist response curve (solid curve) to lower agonist concentrations by increasing affinity and/or increase maximum response by increasing efficacy. Dashed curves are 2 examples out of many possible curves after PAM addition. Arrows show the approximate direction of the shifts in curves.[4]
![PAMs shift initial agonist response curve (solid curve) to lower agonist concentrations by increasing affinity and/or increase maximum response by increasing efficacy. Dashed curves are 2 examples out of many possible curves after PAM addition. Arrows show the approximate direction of the shifts in curves.[4]](http://upload.wikimedia.org/wikipedia/commons/thumb/3/38/Positive_allosteric_modulator_plot.svg/280px-Positive_allosteric_modulator_plot.svg.png)
PAM-agonists work like PAMs, but are agonists themselves. Thus they induce a response even at minimal concentrations of the agonists they modulate.[4]
![PAM-agonists work like PAMs, but are agonists themselves. Thus they induce a response even at minimal concentrations of the agonists they modulate.[4]](http://upload.wikimedia.org/wikipedia/commons/thumb/0/0f/Positive_allosteric_modulator_agonist_plot.svg/280px-Positive_allosteric_modulator_agonist_plot.svg.png)
PAM-antagonists increase agonist affinities and shift their curves to lower concentrations, but as they work as antagonists, they also lower maximum responses.[4]
![PAM-antagonists increase agonist affinities and shift their curves to lower concentrations, but as they work as antagonists, they also lower maximum responses.[4]](http://upload.wikimedia.org/wikipedia/commons/thumb/7/7e/Positive_allosteric_modulator_antagonist_plot.svg/280px-Positive_allosteric_modulator_antagonist_plot.svg.png)
NAMs shift curves to higher concentrations by decreasing affinities and/or lower maximum responses by decreasing efficacies. If compared to PAMs, the effects of NAMs are inverse.[4]
![NAMs shift curves to higher concentrations by decreasing affinities and/or lower maximum responses by decreasing efficacies. If compared to PAMs, the effects of NAMs are inverse.[4]](http://upload.wikimedia.org/wikipedia/commons/thumb/c/ca/Negative_allosteric_modulator_plot.svg/280px-Negative_allosteric_modulator_plot.svg.png)
NAM-agonists work like NAMs, but are agonists themselves. Thus they induce a response even at minimal concentrations of the agonists they modulate.[4]
![NAM-agonists work like NAMs, but are agonists themselves. Thus they induce a response even at minimal concentrations of the agonists they modulate.[4]](http://upload.wikimedia.org/wikipedia/commons/thumb/8/81/Negative_allosteric_modulator_agonist_plot.svg/280px-Negative_allosteric_modulator_agonist_plot.svg.png)
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.[4]
Efficacy increasing modulators increase maximum efficacy of partial agonists. Full agonists already activate receptors fully so modulators don't affect their maximum efficacy, but somewhat shift their response curves to lower agonist concentrations.[4]
Medical importance[edit]
Benefits[edit]
Related receptors have orthosteric sites that are very similar in structure, as mutations within this site may especially lower receptor function. This can be harmful to organisms, so evolution doesn't often favor such changes. Allosteric sites are less important for receptor function, which is why they often have great variation between related receptors. This is why, in comparison to orthosteric drugs, allosteric drugs can be very specific, i.e. target their effects only on a very limited set of receptor types. However, such allosteric site variability occurs also between species so the effects of allosteric drugs vary greatly between species.[11]
Modulators can't turn receptors fully on or off as modulator action depends on endogenous ligands like neurotransmitters, which have limited and controlled production within body. 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.[4] This also allows receptors to activate at prescribed times (i.e. in response to a stimulus) instead of being activated constantly by an agonist, irrespective of timing or purpose.[12]
Modulators affect the existing responses within tissues and can allow tissue specific drug targeting. This is unlike orthosteric drugs, which tend to produce a less targeted effect within body on all of the receptors they can bind to.[4]
Some modulators have also been shown to lack the desensitizing effect that some agonists have. Nicotinic acetylcholine receptors, for example, quickly desensitize in the presence of agonist drugs, but maintain normal function in the presence of PAMs.[13]
Applications[edit]
Allosteric modulation has demonstrated as beneficial to many conditions that have been previously difficult to control with other pharmaceuticals. These include: