What is the Hottest and Coolest Molecule?

🏅This topic is related to The Nobel Prize in Physiology or Medicine 2021. 🌶️David Julius discovered TRPV1, a heat-sensing receptor that is activated at temperatures perceived as painful. He used capsaicin, a pungent compound from chili peppers to identify this receptor. ❄️David Julius and Ardem Patapoutian also identify TRPM8, a receptor that was shown to be activated by cold, by using menthol found in mint.

👊I could not include in the image below but another important discovery by Ardem Patapoutian is “Piezo” the receptor activated by mechanical stimuli in the skin and internal organs. Piezo was named after the Greek word for pressure (í; píesi).

🌶️🌶️🌶️Resiniferatoxin (RTX) is a phorbol ester found in the irritant lattices of the Moroccan cactus. The Scoville scale is a measurement of the pungency originally defined by a dilution factor when diluted with sugar water until no pungency is felt. The Scoville scale of Resiniferatoxin is 1000 times hotter than pure capsaicin. 

💊Of course, RTX is highly toxic, but its use as a painkiller is also being studied.

❄️TRPM8 are cold sensors in humans that can be activated by cooling (<28 ºC) or some chemicals such as menthol. Menthol is a mono terpene found in mint. Industrial scale synthesis of menthol is possible by asymmetric catalysis. When the menthol touches the skin, you will feel a chilling sensation. Menthol is widely used in gums, candies, toothpaste, over-the-counter medicines, and cigarette flavors.

🧊Scientists developed many menthol derivatives but icilin is a super-cooling agent. Icilin is a synthetic compound that can activate TRPM8 and ~200-fold more potent than menthol!!! ☃️☃️☃️


1. A.Szallasi, P. M. Blumberg, “Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper” Neuroscience, 1989, 30, 515.

2. R. González-Muñiz, et al. “Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer” J. Med. Chem. 2016, 59, 10006.

3. R. González-Muñiz, et al. “Recent Progress in TRPM8 Modulation: An Update” Int. J. Mol. Sci. 2019, 20(11), 2618.

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