Pepper compounds and monoamine oxidase

[polymath]

The compound methylpiperate, a minor component of pepper plants, seems to be a selective MAO-B inhibitor with a Ki value 2-3 times lower than that of piperine...

Methylpiperate derivatives from Piper longum and their inhibition of monoamine oxidase - PubMed

We have previously reported that piperine, a known piperidine alkaloid from Piper longum, competitively inhibited mouse brain MAO-A and MAO-B activities. Piperine also showed in vivo antidepressant-like activity against the tail suspension test. In the present study, we further expanded on the...

www.ncbi.nlm.nih.gov

We have previously reported that piperine, a known piperidine alkaloid from Piper longum, competitively inhibited mouse brain MAO-A and MAO-B activities. Piperine also showed in vivo antidepressant-like activity against the tail suspension test. In the present study, we further expanded on the identification of MAO inhibitors from the fruit of P. longum. Activity-guided fractionation of a methylene chloride soluble extract led to the isolation of three known piperine-related compounds, methylpiperate (1), guineensine (2), and piperlonguminine (3). Of these, methylpiperate (1) and guineensine (2) showed significant MAO inhibitory activities with IC50 values of 3.6 and 139.2 microM, respectively. Furthermore, methylpiperate (1) exhibited a selective inhibitory effect against MAO-B (IC50 value: 1.6 microM) than MAO-A (IC50 value: 27.1 microM). The kinetic study using the Lineweaver-Burk plots analysis suggested that methylpiperate (1) competitively inhibits MAO-A and MAO-B activities with the Ki values of 23.5 and 1.3 microM, respectively.

Piperine from the fruits of Piper longum with inhibitory effect on monoamine oxidase and antidepressant-like activity - PubMed

A bioassay-guided isolation of the ethanol extract from the fruits of Piper longum yielded a known piperidine alkaloid, piperine, as a monoamine oxidase (MAO) inhibitor. Piperine showed an inhibitory effect against MAO-A (IC50 value: 20.9 microM) and MAO-B (IC50 value: 7.0 microM). Kinetic...

www.ncbi.nlm.nih.gov

A bioassay-guided isolation of the ethanol extract from the fruits of Piper longum yielded a known piperidine alkaloid, piperine, as a monoamine oxidase (MAO) inhibitor. Piperine showed an inhibitory effect against MAO-A (IC50 value: 20.9 microM) and MAO-B (IC50 value: 7.0 microM). Kinetic analyses by a Lineweaver-Burk plot clearly indicated that piperine competitively inhibited MAO-A and MAO-B with Ki values of 19.0+/-0.9 microM and 3.19+/-0.5 microM, respectively. The inhibition by piperine was found to be reversible by dialysis of the incubation mixture. In addition, the immobility times in the tail suspension test were significantly reduced by piperine, similar to that of the reference antidepressant fluoxetine, without accompanying changes in ambulation when assessed in an open-field. These results suggest that piperine possesses potent antidepressant-like properties that are mediated in part through the inhibition of MAO activity, and therefore represent a promising pharmacotherapeutic candidate as an antidepressant agent.

Could this mean that methylpiperate could actually be a useful selegiline-like compound? It seems unclear, for instance, whether it metabolized too quickly to be of practical use. Or whether there's enough of it in any commercial plant extract to make any difference.

 

[d1nach]

Do you have the Ki values for selegiline and the quantity of methylpiperate in say mg/gram of commercial pepper .

 

[sekio]

Methyl piperate looks like a poor drug... logP of a lot and no basic nitrogen, a bunch of metabolic handles, etc... not looking good for an in vivo drug

 

[Bravoncius Roxford]

The compound methylpiperate, a minor component of pepper plants, seems to be a selective MAO-B inhibitor with a Ki value 2-3 times lower than that of piperine...

Methylpiperate derivatives from Piper longum and their inhibition of monoamine oxidase - PubMed

We have previously reported that piperine, a known piperidine alkaloid from Piper longum, competitively inhibited mouse brain MAO-A and MAO-B activities. Piperine also showed in vivo antidepressant-like activity against the tail suspension test. In the present study, we further expanded on the...

www.ncbi.nlm.nih.gov

Piperine from the fruits of Piper longum with inhibitory effect on monoamine oxidase and antidepressant-like activity - PubMed

A bioassay-guided isolation of the ethanol extract from the fruits of Piper longum yielded a known piperidine alkaloid, piperine, as a monoamine oxidase (MAO) inhibitor. Piperine showed an inhibitory effect against MAO-A (IC50 value: 20.9 microM) and MAO-B (IC50 value: 7.0 microM). Kinetic...

www.ncbi.nlm.nih.gov

Could this mean that methylpiperate could actually be a useful selegiline-like compound? It seems unclear, for instance, whether it metabolized too quickly to be of practical use. Or whether there's enough of it in any commercial plant extract to make any difference.

Piperine and methylpiperine are weak MAOIs in vitro. But just because something shows activity in vitro, it does not mean that it will have activity in vivo. It is a long way from your mouth to the mitochondria inside cells where MAO is located. The systemic bioavailability of piperine is very poor. Lots of things affect bioavailability: stomach PH, transporter carriers in the G.I tract, rate of first by-pass metabolism in the liver, degree of protein binding in the bloodstream, ability to permeate lipids(important for access through the blood-brain barrier). This is why it costs millions of Dollars and takes years to develop effective pharmaceutical drugs: because finding molecules with the combination of high potency with high oral bioavailability is not easy. This is espcially true for drugs that are supposed to be psychoactive, because the blood-brain barrier is an added problem that must be bypassed. Sure, piperine "on paper" would inhibit MAO-B if you took close to 100 grams of it in a single sitting. But given it's poor oral bioavailability, even this ridiculous dose will give you only a little MAO-B inhibition peripherically. The only thing that piperine is truly good at is increasing the bioavailability of other molecules since it is a potent inhibitor of certain liver enzymes.

Now, compare piperine to rasagiline, a potent synthetic irreversible MAO-B inhibitor used as monotherapy for early Parksinon's disease. The IC50 of rasagiline for inhibition of MAO-B is 0.5 nmol in vitro, and 4.5 nmol in vivo. And it's bioavailability is 36%, meaning that at least about a third of the drug reaches the target enzyme inside the mitochondria of neurons of the striatum. A single 1 mg dose of rasagiline causes irreversible inhibition of 50% of MAO-B in platelets. That's from a measly 1 mg dose. I doubt very much that even one kilogram of pure piperine could do that, given that it is 10,000 X weaker and 100 X less bioavailable. Most natural compounds cannot even come close to pharmaceuticals.

 

[polymath]

Methyl piperate looks like a poor drug... logP of a lot and no basic nitrogen, a bunch of metabolic handles, etc... not looking good for an in vivo drug

Yeah, the piperine derivative antiepilepsirine (figure below), which has actual clinical use, has one less double bond and is likely to be metabolized more slowly...

In this article (abstract and Sci-Hub link), both piperine and antiepilepsirine were found to cause in vivo inhibition of MAO-B...

Antidepressant-like effects of piperine and its derivative, antiepilepsirine - PubMed

In the present study, antidepressant-like effects of piperine (PIP) and its derivative, antiepilepsirine (AES), were investigated in two depressive models: forced swimming test (FST) and tail suspension test (TST). To further explore the mechanisms underlying their antidepressant-like...

www.ncbi.nlm.nih.gov

Sci-Hub | Antidepressant-like effects of piperine and its derivative, antiepilepsirine. Journal of Asian Natural Products Research, 9(5), 421–430 | 10.1080/10286020500384302

However, only antiepilepsirine increased the amount on dopamine in the brain. The kind of amounts of pepper compounds or raw black pepper that can believably cause some actual effects will easily cause a reflux esophagitis as a side effect. At least they should be swallowed in a capsule that doesn't dissolve before it gets past the stomach.




Edit: And the dose of piperine or AES needed for notable MAO-B inhibition was only 10 mg/kg, which shouldn't be too much for someone to take, unless there's something questionable in the article and the journal...

 

[Skorpio]

The studies don't seem to have the greatest controls- they use fluoxetine as a negative control, but do not use a positive control for Mao-A/B inhibition. Adding a drug such as phenelzine or selegiline would give a good reference value for the amount of inhibition for a proper Maoi. (Also if i was doing this experiment I'd add in some reversible maois too such as harmaline and moclobemide.


I am not very convinced either by their results of fluoxetine increasing dopamine to a similar degree as AES.

Finally the effect size for a lot of the experiments seems pretty low. Some of the significant values for AED maoi activity dovetailed with the control when their errors were included. Adding positive controls would really help me believe the effect size though, I really cant stress this enough.

Finally, I do admit that I came into reading the paper with bias because it's in the journal of Asian natural products research, and super low impact journals tend to publish low impact research (on one random impact site it had an impact factor of 35 while journal of biological chemistry had one of 477 and nature had one of 1096).

 

[polymath]

Thanks for the detailed answer. I need to see whether there are other reports of in vivo effectiveness of those compounds. The affinity of piperine to the MAO-B enzyme doesn't seem to be any worse than that of caffeine to adenosine receptors...

The methylpiperate compound doesn't necessarily taste peppery, because it doesn't have the piperidine ring in it. Even unsubstituted piperidine has that same characteristic taste AFAIK.

 

[Skorpio]

Caffeine is a fairly weak drug though. In general micromolar affinity means that the drug will be way more prone to off target effects and general toxicity. Caffeine has a pretty large range of other targets once you start talking about milimolar concentrations.


Plus selegiline is an irreversible maoi, so its inhibition is much more of a steady state thing. The piperine compound is going to be more like harmaline as it doesn't have any obvious reaction groups that would fuck up an mao enzyme.

 

[polymath]

Unfortunately there seem to be no other studies about in vivo MAO inhibition by piperine derivatives. They are more selective for MAO-B, by the way (just mentioning to be sure, I guess that was a typo). There aren't really any obvious symptoms from which someone could deduce that they've ingested an effective dose of a MAO-B inhibitor (unless you smoke half a gram of phenethylamine in a vaporizer and check if your pupils dilate, or something similarly radical...).

 

[Skorpio]

I removed the statement in error from my previous post. Not only did I swap mao b for mao a, but I also used the wrong reference numbers so the statement was not factual.

I will say I am inherently skeptical whenever I read that X herb or spice has maoi activity, because maois have a ton of contra indications, and the lack of reports of adverse effects from people stacking their speed or what have you with piperine and curcumin implies a lack of robust maoi activity.

Another aspect that causes me hesitation when it comes to herbals is the fact that doubling the dose often does not double the effects. That is always a personal indication that the compounds seriously lack either efficacy or bioavailability (looking at you valerian).

 

[polymath]

Yeah, there are many publications where pharmacologists from some poor country are trying to promote their own natural products by showing they have some anxiolytic or other useful effect. Ginger extract, various kinds of herbs and so on. And when you read the article carefully, it seems that the mere alcohol content of their plant extracts is enough to explain that anti-anxiety or anticonvulsant effect they observed.

Edit: The ester formed from para-hydroxycinnamic acid and 2-phenylethyl alcohol seems to be a MAO-B inhibitor with 0.013 micromolar affinity... The first of those precursors is found in some plant sources and the other one is a fusel alcohol produced from phenylalanine in fermentation.

Sci-Hub: article not found