pharmacology Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur betwee ...

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, a ...

, allosteric modulators are a group of substances that bind to a

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

to change that receptor's response to stimuli. Some of them, like

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

s or

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

, function as psychoactive 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 (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the receptor would bind (i.e., an ''orthosteric site''). Modulators and agonists can both be called receptor

ligands In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...

. 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 Pa ...

), increasing its ability to activate the receptor (i.e.

efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as '' effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made betwee ...

), 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. 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 Pa ...

is the ability of a substance to bind to a

Efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as '' effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made betwee ...

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

. If efficacy is zero, the substance is considered an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.

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 (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

, 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

s like

diazepam Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...

alprazolam Alprazolam, sold under the brand name Xanax among others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly prescribed in the ...

and chlordiazepoxide, which modulate GABA_A-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 p ...

. 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 Research chemicals are chemical substances which scientists use for medical and scientific research purposes. One characteristic of a research chemical is that it is for laboratory research use only; a research chemical is not intended for human ...

, 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

s and barbiturates, which are GABA_A receptor positive allosteric modulators. Benzodiazepines like

bind between α and γ subunits of the GABA_A 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 (electrophysiol ...

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 (AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic glutamate receptor (iGluR) and predominantly sodium ion channel that mediates fast excitator ...

s 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 Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

, 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 an agonist. This is often caused by repeated or intense exposures to an agonist. Eliminating or reducing this phenomenon increases 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'', ...

go> 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. File:Positive allosteric modulator agonist plot.svg, PAM-agonists work like PAMs, but are agonists themselves. Thus they induce a response even at minimal concentrations of the agonists they modulate. File:Positive allosteric modulator antagonist plot.svg, PAM-antagonists increase agonist affinities and shift their curves to lower concentrations, but as they work as antagonists, they also lower maximum responses. File:Negative allosteric modulator plot.svg, 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. File:Negative allosteric modulator agonist plot.svg, NAM-agonists work like NAMs, but are agonists themselves. Thus they induce a response even at minimal concentrations of the agonists they modulate.

Medical importance

Benefits

Related receptors have orthosteric sites that are very similar in structure, as

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s within this site may especially lower receptor function. This can be harmful to organisms, so

evolution Evolution is the change in the heritable Phenotypic trait, characteristics of biological populations over successive generations. It occurs when evolutionary processes such as natural selection and genetic drift act on genetic variation, re ...

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

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

s, which have limited and controlled production within body. This can lower

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

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 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. 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. Some modulators have also been shown to lack the desensitizing effect that some agonists have.

Nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are Receptor (biochemistry), receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the c ...

s, for example, quickly desensitize in the presence of agonist drugs, but maintain normal function in the presence of PAMs.

Applications

Allosteric modulation has demonstrated as beneficial to many conditions that have been previously difficult to control with other pharmaceuticals. These include: * reducing the negative symptoms (deficits) associated with

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

by using experimental mGluR5 positive modulators like 4-nitro-''N''-(1,3-diphenyl-1''H''-pyrazol-5-yl)benzamide ( VU-29). * reducing anxiety by positively modulating GABA receptors. * reducing the intensity of sleep disorders by positively regulating GABA receptors. * reducing depressive symptoms of

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

and

by positively modulating dopamine receptors. Examples include DETQ, DPTQ and LY3154207, which are experimental D₁ receptor positive modulators.

References

{{Neuromodulation Neuropharmacology