Weird drug fact: Menthol is an analogue of Propofol and also has GABAa & K-opioid activity

[Jabberwocky]

Menthol: a natural analgesic compound - PubMed

Menthol, after topical application, causes a feeling of coolness due to stimulation of 'cold' receptors by inhibiting Ca++ currents of neuronal membranes. Since Ca++ channel blockers are endowed with analgesic properties, the aim of the present study was to investigate the potential...

pubmed.ncbi.nlm.nih.gov

Menthol shares general anesthetic activity and sites of action on the GABA(A) receptor with the intravenous agent, propofol - PubMed

Menthol and related compounds were investigated for modulation of recombinant human gamma-aminobutyric acid type A (GABA(A), alpha(1)beta(2)gamma(2s)) receptor currents expressed in Xenopus oocytes. Sub-maximal (EC(20)) GABA currents were typically enhanced by co-applications of 3-300 microM...

pubmed.ncbi.nlm.nih.gov

I love stumbling on random drug facts like this, it makes me even more fascinated with chemistry/biology

this is merely fun coincidence, learning material - it's not that particularly interesting I just thought menthol was very inert

title is slightly misleading, it shares sites but not action, but still similar chemicals (don't start boofing vick's vapo rub...)

 

[Bare_head]

So menthol actually causes that cooling effect from the drug itsself ?

Like the mint? This is interesting in itself!

I need to go down the rabbit hole of how we taste things now. Mind blown

 

[negrogesic]

Yeah a bunch of these have gabaergic activity, like the closely related thymol (of which menthol is a hydrogenated variant). Propofol is a very simple structure, 2,6-diisopropylphenol, easy to remember

 

[Skorpio]

Here's something I found out today, the transient receptor potential cation channel subfamily M (melastatin) member 3 (TRPM3) is also known as the cold and menthol receptor 1 (CMR1), a transducer of cold somatosensation in humans. It also works in conjunction (unsuprisingly) with capsaicin receptors.

(Menthol)^-1 ≈ capsaicin

Also, the same receptor is a marker for prostate cancer (as its expression is increased in the early stages of prostate cancer). This finding resulted in some menthol-receptor ligands with an EC50 2000 times lower than menthol itself; I wonder if tasting it would feel like putting your tongue in a cryogenic liquid, with the plus-side being that your tongue doesn't dry up and fall off. WS-12 (N-(4-Methoxyphenyl)-5-methyl-2-(propan-2-yl)cyclohexane-1-carboxamide) had the highest affinity in this study. There is a super-agonist known as icilin (3-(2-Hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one) which is 200 times more potent than menthol...Anyways, these agonists seem to be very effective antipruritics. I'm intrigued, perhaps I can soak the filters of my cigarettes with icilin and give them to my friends as an April fools joke.

This year's medicine Nobel was for the discovery of trpv1 (and some other sensory receptors).

Trp channels very interesting. They ate nonselective for cations so let both calcium and sodium ions through. This can cause in activation at high levels of channel opening.

Trpv1 has its own super agonist (probably so spicy ittl ablate your taste buds)

Resiniferatoxin - Wikipedia

en.m.wikipedia.org

A thing I've always found curious is the interplay between trpv1 and cannabinoid signaling. Anandamide and 2 arachidonyl glycerol are both endogenous agonists at both receptor types, and birth receptor types are involved in perception of pain and inflammation.

 

[allone]

yeah i wish you pleasant times enjoying such interesting findings because they are useless and lead to nowhere. when i was young and not as depressed I LOVED finding out natural compounds doing things nobody knew they were doing. UNTIL i got older and depressed and realized they are all useless and thats why nobody cares to know about them haha

 

[Skorpio]

yeah i wish you pleasant times enjoying such interesting findings because they are useless and lead to nowhere. when i was young and not as depressed I LOVED finding out natural compounds doing things nobody knew they were doing. UNTIL i got older and depressed and realized they are all useless and thats why nobody cares to know about them haha

That's rich.

I like these things because they are interesting and highlight the complexities of life, not just because they are gonna cure me of whatever ails.

 

[4meSM]

Menthol and many other monoterpenoids have pharmacological activities, but most of them have a very low bioavailability as well (partly because they tend to be very hydrophobic). That being said, a phenol (propofol) is actually quite different from a secondary alcohol such as menthol, it looks more like thymol. Though, structurally speaking, "all" monoterpenoids have skeletons with 10 carbon atoms while propofol has 12.

This year's medicine Nobel was for the discovery of trpv1 (and some other sensory receptors).

Trp channels very interesting. They ate nonselective for cations so let both calcium and sodium ions through. This can cause in activation at high levels of channel opening.

Trpv1 has its own super agonist (probably so spicy ittl ablate your taste buds)

Resiniferatoxin - Wikipedia

en.m.wikipedia.org

A thing I've always found curious is the interplay between trpv1 and cannabinoid signaling. Anandamide and 2 arachidonyl glycerol are both endogenous agonists at both receptor types, and birth receptor types are involved in perception of pain and inflammation.

Yeah that's a very interesting molecule, and it's actually a terpene as well! It's a daphnane-type diterpenoid, one of the few classes of natural compounds where one is able to find 3 oxygen atoms bound to the same carbon.

 

[Bare_head]

Wow this stuff blows my mind whilst sucking on a jakemans menthol cough sweet

 

[polymath]

I believe that if you were to dose enough menthol to cause even mild general anesthetic-like effects, you could feel the minty taste in your mouth just from so high concentration of menthol being in your bloodstream.

 

[bingey]

Yeah a bunch of these have gabaergic activity, like the closely related thymol (of which menthol is a hydrogenated variant). Propofol is a very simple structure, 2,6-diisopropylphenol, easy to remember

isn't thymol the active constituent of black onion seed oil?

 

[negrogesic]

isn't thymol the active constituent of black onion seed oil?

That's thymoquinone you're thinking of

 

[Xorkoth]

Also it's black cumin seed, not black onion.

 

[allone]

thymoquinone is said to be quite bioactive.

 

[4meSM]

As far as sedative effects go, I think the bicyclic monoterpenoids are the most promising ones, especially myrtenol and verbenol which are fairly potent gaba allosteric modulators.
The problem is that they're veeeery hydrophobic... You need about 1L of water to dissolve 1.5g of myrtenol.

https://onlinelibrary.wiley.com/doi/full/10.1002/mnfr.201300420

Carvacrol is another cool one as well, that one is actually really similar to propofol.

 

[allone]

As far as sedative effects go, I think the bicyclic monoterpenoids are the most promising ones, especially myrtenol and verbenol which are fairly potent gaba allosteric modulators.
The problem is that they're veeeery hydrophobic... You need about 1L of water to dissolve 1.5g of myrtenol.

https://onlinelibrary.wiley.com/doi/full/10.1002/mnfr.201300420

Carvacrol is another cool one as well, that one is actually really similar to propofol.

carvacrol is widely present in most herbs. especially their oils. like thyme and oregano. oregano oil is very high on carvacrol. what do you think will happen consuming high amounts of oregano oil??

 

[4meSM]

carvacrol is widely present in most herbs. especially their oils. like thyme and oregano. oregano oil is very high on carvacrol. what do you think will happen consuming high amounts of oregano oil??

Unfortunately many of them are really bad drug-like compounds (at least in their raw form), the effective dose is too high and they lack selectivity. For instance, carvacrol also has antimicrobial and anti-cancer properties (in-vitro), and just as it can kill microorganisms and cancer cells it can also damage healthy cells.
One should never ingest large quantities of essential oils, if you're lucky you can expect a lot of vomiting and nausea. Worse case scenario: seizures, organ failure, death.

Phenolic compounds in essential oils are often praised due to their antioxidant properties. However, just because they act as strong antioxidants in-vitro doesn't mean they will reduce oxidative stress when ingested, in fact the opposite is often true. (Though I can't really generalize because it depends on the compound in question and the dose)

Here's a review on carvacrol (the full text is available with the EndNote click browser extension):
https://onlinelibrary.wiley.com/doi/10.1002/ptr.6103

 

[plumbus-nine]

The Russian have menthol pills for anxiety. Once I ordered some and tried them but no effect. Maybe I should have dosed higher.

 

[allone]

carvacrol and dopamine in the rat; https://pubmed.ncbi.nlm.nih.gov/23708230/

When single doses were used (150 and 450 mg/kg p.o.), dopamine content was increased in the prefrontal cortex at both dose levels. On the contrary, a significant dopamine reduction in hippocampus of animals treated with 450 mg/kg of carvacrol was found.

If regularly ingested in low concentrations, it might determine feelings of well-being and could possibly have positive reinforcer effects.