Allosteric modulator

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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 alcoholic beverages, 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]

Contents

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]

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. [4] 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. If efficacy is zero, the substance is considered an antagonist. [1]

Orthosteric agonist (A) binds to orthosteric site (B) of a receptor (E). Allosteric modulator (C) binds to allosteric site (D). Modulator increases/lowers the affinity (1) and/or efficacy (2) of an agonist. Modulator may also act as an agonist and yield an agonistic effect (3). Modulated orthosteric agonist affects the receptor (4). Receptor response (F) follows. Allosteric modulator.svg
Orthosteric agonist (A) binds to orthosteric site (B) of a receptor (E). Allosteric modulator (C) binds to allosteric site (D). Modulator increases/lowers the affinity (1) and/or efficacy (2) of an agonist. Modulator may also act as an agonist and yield an agonistic effect (3). Modulated orthosteric agonist affects the receptor (4). Receptor response (F) follows.

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. [2] 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. [4] Allosteric modulators can also stabilize one of the normal configurations of a receptor. [5]

In practice, modulation can be complicated. A modulator may function as a partial agonist, meaning it doesn't need the agonist it modulates to yield agonistic effects. [6] 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. [4]

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. [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:

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.[ citation needed ]

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. [2] Examples of such modulators include benzodiazepines and barbiturates, which are GABAA receptor positive allosteric modulators. Benzodiazepines like diazepam 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 bind β domains and increase the duration of each opening, but not the frequency. [9]

Modulating unbinding

CX614, a PAM for an AMPA receptor binding to an allosteric site and stabilizing the closed conformation AMPA receptor- Allosteric Modulation.jpg
CX614, a PAM for an AMPA receptor binding to an allosteric site and stabilizing the closed conformation

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. [5] [9]

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. [5]

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. [10]

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. [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

Benefits

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

Allosteric modulation has demonstrated as beneficial to many conditions that have been previously difficult to control with other pharmaceuticals. These include:

See also

Related Research Articles

<span class="mw-page-title-main">Allosteric regulation</span> Regulation of enzyme activity

In biochemistry, allosteric regulation is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.

<span class="mw-page-title-main">Agonist</span> Chemical which binds to and activates a biochemical receptor

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 agonist, while an inverse agonist causes an action opposite to that of the agonist.

<span class="mw-page-title-main">Receptor (biochemistry)</span> Protein molecule receiving signals for a cell

In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a receptor and produce physiological responses such as change in the electrical activity of a cell. For example, GABA, an inhibitory neurotransmitter inhibits electrical activity of neurons by binding to GABAA receptors. There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration. Relaying sends the signal onward, amplification increases the effect of a single ligand, and integration allows the signal to be incorporated into another biochemical pathway.

<span class="mw-page-title-main">Receptor antagonist</span> Type of receptor ligand or drug that blocks a biological response

A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of receptor proteins. They are sometimes called blockers; examples include alpha blockers, beta blockers, and calcium channel blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors.

<span class="mw-page-title-main">Pharmacodynamics</span> Area of Academic Study

Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs. The effects can include those manifested within animals, microorganisms, or combinations of organisms.

<span class="mw-page-title-main">Ligand-gated ion channel</span> Type of ion channel transmembrane protein

Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl) and, to a lesser extent, bicarbonate ions (HCO3). Depending on the membrane potential and the ionic concentration difference, this can result in ionic fluxes across the pore. If the membrane potential is higher than the equilibrium potential (also known as the reversal potential) for chloride ions, when the receptor is activated Cl will flow into the cell. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring at the postsynaptic cell. The reversal potential of the GABAA-mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABAB IPSP (-100 mV).

Neuropharmacology is the study of how drugs affect function in the nervous system, and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain. Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others.

<span class="mw-page-title-main">Ligand (biochemistry)</span> Substance that forms a complex with a biomolecule

In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ligare, which means 'to bind'. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein. The binding typically results in a change of conformational isomerism (conformation) of the target protein. In DNA-ligand binding studies, the ligand can be a small molecule, ion, or protein which binds to the DNA double helix. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure.

<span class="mw-page-title-main">Bretazenil</span> Chemical compound

Bretazenil (Ro16-6028) is an imidazopyrrolobenzodiazepine anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988. It is most closely related in structure to the GABA antagonist flumazenil, although its effects are somewhat different. It is classified as a high-potency benzodiazepine due to its high affinity binding to benzodiazepine binding sites where it acts as a partial agonist. Its profile as a partial agonist and preclinical trial data suggests that it may have a reduced adverse effect profile. In particular bretazenil has been proposed to cause a less strong development of tolerance and withdrawal syndrome. Bretazenil differs from traditional 1,4-benzodiazepines by being a partial agonist and because it binds to α1, α2, α3, α4, α5 and α6 subunit containing GABAA receptor benzodiazepine receptor complexes. 1,4-benzodiazepines bind only to α1, α2, α3 and α5GABAA benzodiazepine receptor complexes.

<span class="mw-page-title-main">Schild equation</span>

In pharmacology, Schild regression analysis, based upon the Schild equation, both named for Heinz Otto Schild, are tools for studying the effects of agonists and antagonists on the response caused by the receptor or on ligand-receptor binding.

<span class="mw-page-title-main">Adrenergic antagonist</span>

An adrenergic antagonist is a drug that inhibits the function of adrenergic receptors. There are five adrenergic receptors, which are divided into two groups. The first group of receptors are the beta (β) adrenergic receptors. There are β1, β2, and β3 receptors. The second group contains the alpha (α) adrenoreceptors. There are only α1 and α2 receptors. Adrenergic receptors are located near the heart, kidneys, lungs, and gastrointestinal tract. There are also α-adreno receptors that are located on vascular smooth muscle.

<span class="mw-page-title-main">GABA receptor agonist</span>

A GABA receptor agonist is a drug that is an agonist for one or more of the GABA receptors, producing typically sedative effects, and may also cause other effects such as anxiolytic, anticonvulsant, and muscle relaxant effects. There are three receptors of the gamma-aminobutyric acid. The two receptors GABA-α and GABA-ρ are ion channels that are permeable to chloride ions which reduces neuronal excitability. The GABA-β receptor belongs to the class of G-Protein coupled receptors that inhibit adenylyl cyclase, therefore leading to decreased cyclic adenosine monophosphate (cAMP). GABA-α and GABA-ρ receptors produce sedative and hypnotic effects and have anti-convulsion properties. GABA-β receptors also produce sedative effects. Furthermore, they lead to changes in gene transcription.

Receptor theory is the application of receptor models to explain drug behavior. Pharmacological receptor models preceded accurate knowledge of receptors by many years. John Newport Langley and Paul Ehrlich introduced the concept that receptors can mediate drug action at the beginning of the 20th century. Alfred Joseph Clark was the first to quantify drug-induced biological responses. So far, nearly all of the quantitative theoretical modelling of receptor function has centred on ligand-gated ion channels and G protein-coupled receptors.

<span class="mw-page-title-main">Homologous desensitization</span> When a receptor decreases its response to an agonist at high concentration

Homologous desensitization occurs when a receptor decreases its response to an agonist at high concentration. It is a process through which, after prolonged agonist exposure, the receptor is uncoupled from its signaling cascade and thus the cellular effect of receptor activation is attenuated.

<span class="mw-page-title-main">Intrinsic activity</span> Measure of relative response to a drug

Intrinsic activity (IA) and efficacy refer to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its molecular target, and the EC50, which is a measure of the potency of the drug and which is proportional to both efficacy and affinity. This use of the word "efficacy" was introduced by Stephenson (1956) to describe the way in which agonists vary in the response they produce, even when they occupy the same number of receptors. High efficacy agonists can produce the maximal response of the receptor system while occupying a relatively low proportion of the receptors in that system. There is a distinction between efficacy and intrinsic activity.

<span class="mw-page-title-main">Org 27569</span> Chemical compound

Org 27569 is a drug which acts as a potent and selective negative allosteric modulator of the cannabinoid CB1 receptor. Studies in vitro suggest that it binds to a regulatory site on the CB1 receptor target, causing a conformational change that increases the binding affinity of CB1 agonists such as CP 55,940, while decreasing the binding affinity of CB1 antagonists or inverse agonists such as rimonabant. However while Org 27569 increases the ability of CB1 agonists to bind to the receptor, it decreases their efficacy at stimulating second messenger signalling once bound, and so in practice behaves as an insurmountable antagonist of CB1 receptor function.

GABA<sub>A</sub> receptor positive allosteric modulator

In pharmacology, GABAA receptor positive allosteric modulators, also known as GABAkines or GABAA receptor potentiators, are positive allosteric modulator (PAM) molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system.

A receptor modulator, or receptor ligand, is a general term for a substance, endogenous or exogenous, that binds to and regulates the activity of chemical receptors. They are ligands that can act on different parts of receptors and regulate activity in a positive, negative, or neutral direction with varying degrees of efficacy. Categories of these modulators include receptor agonists and receptor antagonists, as well as receptor partial agonists, inverse agonists, orthosteric modulators, and allosteric modulators, Examples of receptor modulators in modern medicine include CFTR modulators, selective androgen receptor modulators (SARMs), and muscarinic ACh receptor modulators.

<span class="mw-page-title-main">AMPA receptor positive allosteric modulator</span>

AMPA receptor positive allosteric modulators are positive allosteric modulators (PAMs) of the AMPA receptor (AMPR), a type of ionotropic glutamate receptor which mediates most fast synaptic neurotransmission in the central nervous system.

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