In pharmacology and biochemistry, allosteric modulators are a group of substances. Some of them, like benzodiazepines, are drugs. A modulator binds to a site in some receptor. This site (i.e., an allosteric site) is not the same one to which an endogenous activator of the receptor would bind (i.e., an orthosteric site). This natural activator could be a neurotransmitter. Receptor activators and inactivators are called agonists. Modulators are either positive, negative or neutral. Positive types increase and negative types lower the probability that an agonist will bind to a receptor (i.e. affinity) and/or its ability activate/inactivate the receptor (i.e. efficacy). Neutral types don't affect agonist activity, but can stop other modulators from binding to a receptor. Some modulators also works as allosteric agonists. Modulators and agonists can be called receptor ligands.
The term "allosteric" comes from the Greek roots allos (other) and stereos (solid), and can be translated as "different shape".
In the context of modulators, affinity is the ability of a substance to bind to a receptor. Binding is not enough for activation, and the ability of a substance to activate a receptor is efficacy. If efficacy is zero, the substance is an antagonist. Receptor activators have positive efficacy and are agonists. Inactivators have negative efficacy and are inverse agonists. Latter are a subgroup of agonists. Antagonists inhibit the effects of inverse agonists and other agonists.
Allosteric modulators increase or lower affinity and/or efficacy of an agonist. A modulator may also increase affinity and lower efficacy or vice versa. The site to which endogenous agonists bind to is named the orthosteric site. Modulators don't bind to this site. They bind to any other suitable sites, which are named allosteric sites. Upon binding, modulators change the three-dimensional structure (i.e. conformation) of the receptor. The orthosteric site also changes, which changes the capabilities of an agonist.
In practice, modulation can be complicated. A modulator may function as a partial agonist. It doesn't need the agonist it modulates to yield agonistic effects. Also, modulation may not affect affinity or efficacy of different agonists equally. Even if a group of different agonists bind to the same receptor, some of the agonists might not be modulated by some modulators.
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. There are 18 (=2*3*3) if neutral modulator type is also counted.
For all practical considerations, these combinations can be generalized only to 5 classes and 1 neutral:
- positive allosteric modulators (PAM) increase agonist affinity and/or efficacy. Clinical examples are benzodiazepines like diazepam, alprazolam and chlordiazepoxide, which modulate GABAA-receptors, and cinacalcet, which modulates calcium-sensing receptors.
- negative allosteric modulators (NAM) lower agonist affinity and/or efficacy. Maraviroc is a medicine that modulates CCR5. Fenobam, raseglurant and dipraglurant are experimental GRM5 modulators.
- NAM-agonists work like NAMs, but also as agonists with and without the agonists they modulate.
- neutral allosteric modulators don't affect agonist activity, but bind to a receptor and prevent PAMs and other modulators from binding to the same receptor thus inhibiting their modulation. Neutral modulators are also called silent allosteric modulators (SAM) or neutral allosteric ligands (NAL). An example is 5-methyl-6-(phenylethynyl)-pyridine (5MPEP), a research chemical, which binds to GRM5.
Interaction with agonists
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.
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.
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.
PAM-agonists work like PAMs, but are agonists themselves. Thus they induce a response even at minimal concentrations of the agonists they modulate.
PAM-antagonists increase agonist affinities and shift their curves to lower concentrations, but as they work as antagonists, they also lower maximum responses.
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.
NAM-agonists work like NAMs, but are agonists themselves. Thus they induce a response even at minimal concentrations of the agonists they modulate.
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.
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.
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.
- Allosteric regulation
- AMPA receptor positive allosteric modulator
- GABAA receptor positive allosteric modulator
- GABAA receptor negative allosteric modulator
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