Iodoresiniferatoxin (I-RTX) is a strong competitive

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.TRPV1 The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the ''TRPV1'' gene. It was the first isolated member of ...

) receptor. I-RTX is derived from

resiniferatoxin Resiniferatoxin (RTX) is a naturally occurring chemical found in resin spurge ('' Euphorbia resinifera''), a cactus-like plant commonly found in Morocco, and in '' Euphorbia poissonii'' found in northern Nigeria.

(RTX).

Sources

I-RTX can be prepared from RTX by

electrophilic aromatic substitution Electrophilic aromatic substitution (SEAr) is an organic reaction in which an atom that is attached to an aromatic ring, aromatic system (usually hydrogen) is replaced by an electrophile. Some of the most important electrophilic aromatic substitut ...

. Iodide substitutes the 5-position.

Chemistry

Iodination of RTX at the 5-position changes the toxin from an TRPV1-receptor

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 ...

into an TRPV1-receptor antagonist, with only a little lower

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 ...

for TRPV1 than RTX. As RTX, I-RTX belongs to the daphnane family of molecules. The substance is soluble in

DMSO Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula . This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is ...

and in

ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...

. 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.

Target

Initially, iodoresiniferatoxin was thought to be a competitive antagonist of the TRPV1 receptor with high affinity ( ''K''_d = to HEK 293/VR1 and ''K''_d = 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 . The TRPV1 receptor encodes a protein of 838

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s forming a calcium-permeable channel that is activated by

capsaicin Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) (, rarely ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a potent Irritation, irritant for Mammal, mammals, including humans, and produces ...

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 Conductor or conduction may refer to: Biology and medicine * Bone conduction, the conduction of sound to the inner ear * Conduction aphasia, a language disorder Mathematics * Conductor (ring theory) * Conductor of an abelian variety * Condu ...

in afferent pain pathways.{{cite journal , pmid =19305794 , year =2008 , last1 =Premkumar , first1 =LS , last2 =Sikand , first2 =P , title =TRPV1: A Target for Next Generation Analgesics , volume =6 , issue =2 , pages =151–63 , doi =10.2174/157015908784533888 , pmc =2647151 , journal =Current Neuropharmacology

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 ions (Ca2+) contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contraction o ...

concentrations. It also exerts weak, partial agonism on recombinant TRPV1 in vitro. This agonistic effect could be due to

metabolization Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

whereby I-RTX would be deiodinated, converting it into RTX with its respective characteristics. In vivo, I-RTX showed

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

activity in the capsaicin pain test. I-RTX thus is able to block TRPV1 mediated

nociceptive In physiology, nociception , also nocioception; ) is the sensory nervous system's process of encoding noxious stimuli. It deals with a series of events and processes required for an organism to receive a painful stimulus, convert it to a molecular ...

and neurogenic inflammatory responses.

Toxicity

In mice, I-RTX induces dose-dependent

hypothermia Hypothermia is defined as a body core temperature below in humans. Symptoms depend on the temperature. In mild hypothermia, there is shivering and mental confusion. In moderate hypothermia, shivering stops and confusion increases. In severe ...

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

pharmacokinetic Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific subs ...

characteristics.

References

Ion channel toxins Carboxylate esters Orthoesters Benzyl compounds Heterocyclic compounds with 5 rings Methoxy compounds Iodoarenes Diols Isopropenyl compounds