In
pharmacology 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 and ...
, allosteric modulators are a group of substances that bind to a
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
to change that receptor's response to stimulus. Some of them, like
benzodiazepines, 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 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
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Par ...
), 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
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Par ...
is the ability of a substance to bind to a
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
.
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. If efficacy is zero, the substance is considered an
antagonist.
![Allosteric modulator](https://upload.wikimedia.org/wikipedia/commons/b/be/Allosteric_modulator.svg)
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 antagonis ...
, 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 benzodiazepines like ]diazepam
Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, ...
, alprazolam
Alprazolam, sold under the brand name Xanax, among others, is a fast-acting, potent tranquilizer of medium duration in the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring. It is most commonly u ...
and chlordiazepoxide
Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol and other drugs.
Chlordiazepoxide has a medium t ...
, which modulate GABAA-receptors, and cinacalcet
Cinacalcet, sold under the brand name Sensipar among others, is a medication used to treat tertiary hyperparathyroidism, parathyroid carcinoma, and primary hyperparathyroidism. Text was copied from this source which is © European Medicines Agenc ...
, which modulates calcium-sensing receptor
The calcium-sensing receptor (CaSR) is a Class C G-protein coupled receptor which senses extracellular levels of calcium ions. It is primarily expressed in the parathyroid gland, the renal tubules of the kidney and the brain. In the parathyroi ...
s.
** ''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
Maraviroc, sold under the brand names Selzentry (US) and Celsentri (EU), is an antiretroviral medication used to treat HIV infection. It is taken by mouth. It is in the CCR5 receptor antagonist class.
It was approved for medical use in the Un ...
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 p ...
. Fenobam
Fenobam is an imidazole derivative developed by McNeil Laboratories in the late 1970s as a novel anxiolytic drug with an at-the-time-unidentified molecular target in the brain. Subsequently, it was determined that fenobam acts as a potent and s ...
, raseglurant
Raseglurant ( INN) (code name ADX-10059) is a negative allosteric modulator of the mGlu5 receptor and derivative of MPEP which was under development by Addex Therapeutics for the treatment of migraine, gastroesophageal reflux disease, and den ...
and dipraglurant
Dipraglurant ( INN) (code name ADX-48621) is a negative allosteric modulator of the mGlu5 receptor which is under development by Addex Therapeutics for the treatment of Parkinson's disease levodopa-induced dyskinesia (PD-LID). As of 2014, it i ...
are experimental GRM5
Metabotropic glutamate receptor 5 is an excitatory Gq-coupled G protein-coupled receptor predominantly expressed on the postsynaptic sites of neurons. In humans, it is encoded by the ''GRM5'' gene.
Function
The amino acid L-glutamate is the ...
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 benzodiazepines and barbiturates, which are GABAA receptor positive allosteric modulators. Benzodiazepines like diazepam
Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, ...
bind between α and γ subunits of the GABAA receptor ion channels and increase the channel opening frequency, but not the duration of each opening. Barbiturates like phenobarbital
Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ep ...
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 receptors modulated by aniracetam and CX614 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, 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
Cyclothiazide (Anhydron, Acquirel, Doburil, Fluidil, Renazide, Tensodiural, Valmiran), sometimes abbreviated CTZ, is a benzothiadiazide (thiazide) diuretic and antihypertensive that was originally introduced in the United States in 1963 by Eli L ...
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 receptor
The calcium-sensing receptor (CaSR) is a Class C G-protein coupled receptor which senses extracellular levels of calcium ions. It is primarily expressed in the parathyroid gland, the renal tubules of the kidney and the brain. In the parathyroi ...
s 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.