Iodoresiniferatoxin
Encyclopedia
Iodoresiniferatoxin is a strong competitive antagonist
of the Transient Receptor Potential Vanilloid 1 (TRPV1
) receptor. I-RTX is derived from resiniferatoxin
(RTX).
form of resiniferatoxin, which is produced by the Moroccan succulent Euphorbia resinifera
. I-RTX is iodinated at the 5-position and is therefore also called 5-iodoresiniferatoxin.
. Iodide substitutes the 5-position.
into an TRPV1-receptor antagonist, with only a little lower affinity
for TRPV1 than RTX.
As RTX, I-RTX belongs to the daphnane family of molecules.
The substance is soluble in DMSO
and in ethanol
.
Binding of I-RTX is dependent upon temperature and pH
value, as has been shown in research with HEK 293 cells expressing TRPV1. The optimal pH value is around 7.8 to 8.0 and binding increases markedly with temperature up to 37 °C and then decreases at higher temperatures.
= 4.3 ± 0.9 nM to HEK 293/VR1 and Kd = 4.2 ± 1.0 nM to rat spinal cord membranes), but recent research indicated also partial transient agonistic characteristics in the thermoregulatory system in mice, especially in higher concentrations ranging from 1 to 30 µM.
The TRPV1 receptor encodes a protein of 838 amino acid
s forming a calcium-permeable channel
that is activated by capsaicin
but also by noxious heat and low extracellular pH. TRPV1 receptors are expressed in many systems in the central and peripheral nervous system, and have a particularly important role in signal conduction in afferent
pain pathways.
Recent studies also revealed partial TRPV1-agonist-like effects of I-RTX in the thermoregulatory system in mice, increasing intracellular Ca2+
concentrations. It also exerts weak, partial agonism on recombinant TRPV1 in vitro. This agonistic effect could be due to metabolization
whereby I-RTX would be deiodinated, converting it into RTX with its respective characteristics. In vivo, I-RTX showed analgesic
activity in the capsaicin pain test. I-RTX thus is able to block TRPV1 mediated nociceptive
and neurogenic inflammatory responses
.
hypothermia in vivo. A statistically significant difference was reported at doses > 0.1 µmol/kg. The maximal effect was found with a dose of 1 µmol/kg, 60 to 100 minutes after administration. No lethality has been reported in this study.
characteristics.
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
of the Transient Receptor Potential Vanilloid 1 (TRPV1
TRPV1
The transient receptor potential cation channel subfamily V member 1 ', also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene...
) receptor. I-RTX is derived from resiniferatoxin
Resiniferatoxin
Resiniferatoxin is a naturally occurring, ultrapotent capsaicin analog that activates the vanilloid receptor in a subpopulation of primary afferent sensory neurons involved in nociception...
(RTX).
Etymology
I-RTX is an iodinatedIodine
Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....
form of resiniferatoxin, which is produced by the Moroccan succulent Euphorbia resinifera
Euphorbia resinifera
Euphorbia resinifera is a species of spurge native to Morocco, where it occurs on the slopes of the Atlas Mountains.-Growth:It is a shrub growing to 60 cm tall, forming multi-stemmed cushion-shaped clumps up to 2 m wide...
. I-RTX is iodinated at the 5-position and is therefore also called 5-iodoresiniferatoxin.
Source
I-RTX can be prepared from RTX by electrophilic aromatic substitutionElectrophilic aromatic substitution
Electrophilic aromatic substitution EAS is an organic reaction in which an atom, usually hydrogen, appended to an aromatic system is replaced by an electrophile...
. Iodide substitutes the 5-position.
Chemistry
Iodination of RTX at the 5-position changes the toxin from an TRPV1-receptor agonistAgonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
into an TRPV1-receptor antagonist, with only a little lower affinity
Chemical affinity
In chemical physics and physical chemistry, chemical affinity is the electronic property by which dissimilar chemical species are capable of forming chemical compounds...
for TRPV1 than RTX.
As RTX, I-RTX belongs to the daphnane family of molecules.
The substance is soluble in DMSO
Dimethyl sulfoxide
Dimethyl sulfoxide is an organosulfur compound with the formula 2SO. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water...
and in ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
.
Binding of I-RTX is dependent upon temperature and pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
value, as has been shown in research with HEK 293 cells expressing TRPV1. The optimal pH value is around 7.8 to 8.0 and binding increases markedly with temperature up to 37 °C and then decreases at higher temperatures.
Target
Initially, iodoresiniferatoxin was thought to be a competitive antagonist of the TRPV1 receptor with high affinity (KdDissociation constant
In chemistry, biochemistry, and pharmacology, a dissociation constant is a specific type of equilibrium constant that measures the propensity of a larger object to separate reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into...
= 4.3 ± 0.9 nM to HEK 293/VR1 and Kd = 4.2 ± 1.0 nM to rat spinal cord membranes), but recent research indicated also partial transient agonistic characteristics in the thermoregulatory system in mice, especially in higher concentrations ranging from 1 to 30 µM.
The TRPV1 receptor encodes a protein of 838 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s forming a calcium-permeable channel
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
that is activated by capsaicin
Capsaicin
Capsaicin 2CHCH=CH4CONHCH2C6H3-4--3- ) is the active component of chili peppers, which are plants belonging to the genus Capsicum. It is an irritant for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact...
but also by noxious heat and low extracellular pH. TRPV1 receptors are expressed in many systems in the central and peripheral nervous system, and have a particularly important role in signal conduction in afferent
Afferent nerve
In the nervous system, afferent neurons , carry nerve impulses from receptors or sense organs towards the central nervous system. This term can also be used to describe relative connections between structures. Afferent neurons communicate with specialized interneurons...
pain pathways.
Mode of action
The proposed molecular mode of action of TRPV1 antagonists is blocking of the channel pore. Several studies using either capsaicin, pH values < 6 or heat as the agonist have shown that I-RTX works as a strong competitive TRPV1 antagonist in vitro.Recent studies also revealed partial TRPV1-agonist-like effects of I-RTX in the thermoregulatory system in mice, increasing intracellular Ca2+
Calcium in biology
Calcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...
concentrations. It also exerts weak, partial agonism on recombinant TRPV1 in vitro. This agonistic effect could be due to metabolization
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
whereby I-RTX would be deiodinated, converting it into RTX with its respective characteristics. In vivo, I-RTX showed analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
activity in the capsaicin pain test. I-RTX thus is able to block TRPV1 mediated nociceptive
Nociception
Nociception is defined as "the neural processes of encoding and processing noxious stimuli." It is the afferent activity produced in the peripheral and central nervous system by stimuli that have the potential to damage tissue...
and neurogenic inflammatory responses
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
.
Toxicity
In mice, I-RTX induces dose-dependentDose-response relationship
The dose-response relationship, or exposure-response relationship, describes the change in effect on an organism caused by differing levels of exposure to a stressor after a certain exposure time...
hypothermia in vivo. A statistically significant difference was reported at doses > 0.1 µmol/kg. The maximal effect was found with a dose of 1 µmol/kg, 60 to 100 minutes after administration. No lethality has been reported in this study.
Therapeutic use
Clinical research is done on the use of I-RTX as an analgesic agent, although several drawbacks have been mentioned: complex chemical structure, high costs of production, and relatively unfavourable pharmacokineticPharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
characteristics.