Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the
ligand
In coordination chemistry, a ligand is an ion or molecule (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 electr ...
-dependent selectivity for certain
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
pathways relative to a reference ligand (often the endogenous hormone or peptide) at the same
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 ...
.
Functional selectivity can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor.
Functional selectivity, or biased signaling, is most extensively characterized at
G protein coupled receptors
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
(GPCRs).
A number of biased agonists, such as those at muscarinic M2 receptors tested as analgesics
or antiproliferative drugs,
or those at opioid receptors that mediate pain, show potential at various receptor families to increase beneficial properties while reducing side effects. For example, pre-clinical studies with
G protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
biased agonists at the
μ-opioid receptor
The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...
show equivalent efficacy for treating pain with reduced risk for addictive potential and
respiratory depression
Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapnia ...
.
Studies within the chemokine receptor system also suggest that GPCR biased agonism is physiologically relevant. For example, a beta-arrestin biased agonist of the chemokine receptor
CXCR3
Chemokine receptor CXCR3 is a Gαi protein-coupled receptor in the CXC chemokine receptor family. Other names for CXCR3 are G protein-coupled receptor 9 (GPR9) and CD183. There are three isoforms of CXCR3 in humans: CXCR3-A, CXCR3-B and chemokin ...
induced greater chemotaxis of T cells relative to a G protein biased agonist.
Functional vs. traditional selectivity
Functional selectivity has been proposed to broaden conventional definitions of
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 biochemica ...
.
Traditional pharmacology
posits that a
ligand
In coordination chemistry, a ligand is an ion or molecule (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 electr ...
can be either classified as an
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 ...
(full or partial),
antagonist
An antagonist is a character in a story who is presented as the chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
or more recently an
inverse agonist
In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist.
A neutral antagonist has no activity in the absence of an agonist or inverse agon ...
through a specific receptor subtype, and that this characteristic will be consistent with all
effector
Effector may refer to:
*Effector (biology), a molecule that binds to a protein and thereby alters the activity of that protein
* ''Effector'' (album), a music album by the Experimental Techno group Download
* ''EFFector'', a publication of the El ...
(
second messenger
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
) systems coupled to that receptor. While this dogma has been the backbone of ligand-receptor interactions for decades now, more recent data indicates that this classic definition of ligand-protein associations does not hold true for a number of compounds; such compounds may be termed as
mixed agonist-antagonists.
Functional selectivity posits that a ligand may inherently produce a mix of the classic characteristics through a single receptor isoform depending on the effector pathway coupled to that receptor. For instance, a ligand can not easily be classified as an agonist or antagonist, because it can be a little of both, depending on its preferred signal transduction pathways. Thus, such ligands must instead be classified on the basis of their individual effects in the cell, instead of being either an agonist or antagonist to a receptor.
It is also important to note that these observations were made in a number of different
expression systems and therefore functional selectivity is not just an
epiphenomenon
An epiphenomenon (plural: epiphenomena) is a secondary phenomenon that occurs alongside or in parallel to a primary phenomenon. The word has two senses: one that connotes known causation and one that connotes absence of causation or reservation ...
of one particular expression system.
Examples
One notable example of functional selectivity occurs with the
5-HT2A receptor, as well as the
5-HT2C receptor.
Serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
, the main endogenous ligand of
5-HT receptors, is a functionally selective agonist at this receptor, activating
phospholipase C
Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
(which leads to
inositol triphosphate
Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the p ...
accumulation), but does not activate
phospholipase A2
The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glyce ...
, which would result in
arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
signaling. However, the other endogenous compound
dimethyltryptamine
''N'',''N''-Dimethyltryptamine (DMT or ''N'',''N''-DMT, SPL026) is a substituted tryptamine that occurs in many plants and animals, including human beings, and which is both a derivative and a structural analog of tryptamine. It is used as a ...
activates arachidonic acid signaling at the 5-HT
2A receptor, as do many exogenous hallucinogens such as
DOB and
lysergic acid diethylamide
Lysergic acid diethylamide (LSD), also known colloquially as acid, is a potent psychedelic drug. Effects typically include intensified thoughts, emotions, and sensory perception. At sufficiently high dosages LSD manifests primarily mental, vi ...
(LSD). Notably, LSD does not activate IP
3 signaling through this receptor to any significant extent. (Conversely, LSD, unlike serotonin, has negligible affinity for the 5-HT
2C-VGV isoform, is unable to promote calcium release, and is, thus, functionally selective at 5-HT
2C.) Oligomers; specifically 5-HT
2A–
heteromer A heteromer is something that consists of different parts; the antonym of homomeric. Examples are:
Biology
* Spinal neurons that pass over to the opposite side of the spinal cord.
* A protein complex that contains two or more different polypeptide ...
s mediate this effect. This may explain why some direct 5-HT
2 receptor agonists have
psychedelic
Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness (known as psychedelic experiences or "trips").Pollan, Michael (2018). ''How to Change Your Mind: What the New Science of ...
effects, whereas compounds that indirectly increase serotonin signaling at the 5-HT
2 receptors generally do not, for example:
selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.
SSRIs increase the extracell ...
s (SSRIs),
monoamine oxidase inhibitor
Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, espe ...
s (MAOIs), and medications using 5HT
2A receptor agonists that do not have constitutive activity at the mGluR2
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius Dimer ...
, such as
lisuride
Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth.
Side effects of lis ...
.
Tianeptine
Tianeptine, sold under the brand names Stablon and Coaxil among others, is an atypical antidepressant which is used mainly in the treatment of major depressive disorder, although it may also be used to treat anxiety, asthma, and irritable bowel ...
, an
atypical antidepressant
An atypical antidepressant is any antidepressant medication that acts in a manner that is different from that of most other antidepressants. Atypical antidepressants include agomelatine, bupropion, iprindole, mianserin, mirtazapine, nefazod ...
, is thought to exhibit functional selectivity at the
μ-opioid receptor
The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...
to mediate its antidepressant effects.
Oliceridine
Oliceridine, sold under the brand name Olinvyk, is an opioid medication that is used for the treatment of moderate to severe acute pain in adults. It is given by intravenous (IV) injection.
The most common side effects include nausea, vomiting, ...
is a μ-opioid receptor agonist that has been described to be functionally selective towards G protein and away from β-arrestin2 pathways.
However, recent reports highlight that, rather than functional selectivity or 'G protein bias', this agonist has low intrinsic efficacy. ''In vivo'', it has been reported to mediate pain relief without tolerance nor gastrointestinal side effects.
The
delta opioid receptor
Delta commonly refers to:
* Delta (letter) (Δ or δ), a letter of the Greek alphabet
* River delta, at a river mouth
* D (NATO phonetic alphabet: "Delta")
* Delta Air Lines, US
* Delta variant of SARS-CoV-2 that causes COVID-19
Delta may also r ...
agonists
SNC80 and
ARM390 demonstrate functional selectivity that is thought to be due to their differing capacity to cause
receptor internalization.
While SNC80 causes delta opioid receptors to internalize, ARM390 causes very little receptor internalization.
Functionally, that means that the effects of SNC80 (e.g.
analgesia
Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...
) do not occur when a subsequent dose follows the first, whereas the effects of ARM390 persist.
However, tolerance to ARM390's analgesia still occurs eventually after multiple doses, though through a mechanism that does not involve receptor internalization.
Interestingly, the other effects of ARM390 (e.g. decreased anxiety) persist after tolerance to its analgesic effects has occurred.
An example of functional selectivity to bias metabolism was demonstrated for an electron transfer protein
cytochrome P450 reductase
Cytochrome P450 reductase (; also known as NADPH:ferrihemoprotein oxidoreductase, NADPH:hemoprotein oxidoreductase, NADPH:P450 oxidoreductase, P450 reductase, POR, CPR, CYPOR) is a membrane-bound enzyme required for electron transfer from NADP ...
(POR) with binding of small molecule ligands shown to alter the protein conformation and interaction with various redox partner proteins of POR.
See also
*
Signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
*
Second messenger system
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
References
Further reading
*
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*
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{{Pharmacology
Biased ligands
Neurophysiology
Pharmacodynamics
Signal transduction