In
pharmacology
Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemi ...
and
biochemistry
Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology ...
, allosteric modulators are a group of substances that bind to a
receptor to change that receptor's response to stimulus. Some of them, like
benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s, are drugs.
The site that an allosteric modulator binds to (i.e., an ''allosteric site'') is not the same one to which an endogenous
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of the receptor would bind (i.e., an ''orthosteric site''). Modulators and agonists can both be called receptor
ligands.
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.
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.
Introduction
Allosteric modulators can alter the affinity and efficacy of other substances acting on a receptor. A modulator may also increase affinity and lower efficacy or vice versa.
Affinity is the ability of a substance to bind to a
receptor.
Efficacy is the ability of a substance to activate a receptor, given as a percentage of the ability of the substance to activate the receptor as compared to the receptor's endogenous
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
. If efficacy is zero, the substance is considered an
antagonist.

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 generally change the three-dimensional structure (i.e. conformation) of the receptor. This will often cause the orthosteric site to also change, which can alter the effect of an agonist binding.][ Allosteric modulators can also stabilize one of the normal configurations of a receptor.]
In practice, modulation can be complicated. A modulator may function as a partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonist ...
, meaning it doesn't need the agonist it modulates to yield agonistic effects. Also, modulation may not affect the affinities or efficacies of different agonists equally. If a group of different agonists that should have the same action bind to the same receptor, the agonists might not be modulated the same by some modulators.[
]
Classes
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 included.
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 ]benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s like diazepam, alprazolam and chlordiazepoxide, which modulate GABAA-receptors, and cinacalcet, which modulates calcium-sensing receptors.
** ''PAM-agonists'' work like PAMs, but also as agonists with and without the agonists they modulate.[
** ''PAM-antagonists'' work like PAMs, but also function as antagonists and lower the efficacy of the agonists they modulate.][
* ''negative allosteric modulators'' (NAM) lower agonist affinity and/or efficacy.][ Maraviroc is a medicine that modulates ]CCR5
C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines.
In humans, the ''CCR5'' gene that encodes the CCR5 pr ...
. 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.
]
Mechanisms
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.
Modulating binding
Some allosteric modulators induce a conformational change in their target receptor which increases the binding affinity and/or efficacy of the receptor agonist. Examples of such modulators include benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s and barbiturates, which are GABAA receptor positive allosteric modulators. Benzodiazepines like diazepam bind between α and γ subunits of the GABAA receptor ion channel
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...
s and increase the channel opening frequency, but not the duration of each opening. Barbiturates like phenobarbital bind β domains and increase the duration of each opening, but not the frequency.
Modulating unbinding
Some modulators act to stabilize conformational changes associated with the agonist-bound state. This increases the probability that the receptor will be in the active conformation, but does not prevent the receptor from switching back to the inactive state. With a higher probability of remaining in the active state, the receptor will bind agonist for longer. AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synaptic transmission in the ce ...
s modulated by aniracetam and CX614
CX-614 is an ampakine drug developed by Cortex Pharmaceuticals. It has been investigated for its effect on AMPA receptors.
Chronic CX-614 treatments produce rapid increases in the synthesis of the brain-derived neurotrophic factor BDNF which has ...
will deactivate slower, and facilitate more overall cation transport. This is likely accomplished by aniracetam or CX614 binding to the back of the "clam shell" that contains the binding site for glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
, stabilizing the closed conformation associated with activation of the AMPA receptor.
Preventing desensitization
Overall signal can be increased by preventing the desensitization of a receptor. Desensitization prevents a receptor from activating, despite the presence of agonist. This is often caused by repeated or intense exposures to agonist. Eliminating or reducing this phenomenon increasing the receptor's overall activation. 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.
Stabilizing active/inactive conformation
Modulators can directly regulate receptors rather than affecting the binding of the agonist. Similar to stabilizing the bound conformation of the receptor, a modulator that acts in this mechanism stabilizes a conformation associated with the active or inactive state. This increases the probability that the receptor will conform to the stabilized state, and modulate the receptor's activity accordingly. Calcium-sensing receptors can be modulated in this way by adjusting the pH. Lower pH increases the stability of the inactive state, and thereby decreases the sensitivity of the receptor. It is speculated that the changes in charges associated with adjustments to pH cause a conformational change in the receptor favoring inactivation.
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.][
concentration
In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', '' number concentration'' ...]
>
File:Positive allosteric modulator plot.svg, 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.