A readily available, plant-derived MAO-B inhibitor with neuroprotective properties

[Alchemica]

A readily available, plant-derived MAO-B inhibitor with neuroprotective properties

 

Inside the brain, MAOs are present in two isoforms: MAO-A and MAO-B which differ in preferred substrates and regional location. MAO-A preferentially deaminates 5-HT and NE and MAO-B, small amines like benzylamine and phenethylamine. DA and p-tyramine are common substrates of both isoforms. MAO-A is often the target of antidepressant therapies. The activity of MAO-B is generally higher in patients affected by neurodegenerative diseases like Alzheimer's and Parkinson's, as such being used therapeutically, particularly in PD.

 

Renewed interest in the field has come also from the recent findings that MAO-B inhibitors have neuroprotective and antioxidant effects and play a role in delaying apoptotic neuronal death and in protecting crucial mitochondrial functions.

 

 

Figure 1. Structures of some synthetic MAO-B inhibitors

 

A long time ago, I was interested in simple molecules that could effectively and selectively inhibit MAO-B. About the simplest one I could find was Ro 16 6491, a metabolite of moclobemide.

 

Some of the pharmaceutical options such as selegiline have additional non-MAOI benefits such as acting as catecholamine activity enhancers, or for safinamide, inhibition of glutamate release, SERT and DAT, affinity to sigma receptors and blockade of calcium and sodium channels

 

Since then, there has been extensive research around natural products which can inhibit MAO-B but ones that are sufficiently potent, selective and available in pure form for convenient dosing are more limited. Unfortunately, most natural products are generally comparatively poor MAO-B inhibitors relative to synthetic options, in the micromolar-millimolar affinity range.

 

Some classes of natural MAO-B inhibitors include β-carbolines, flavonoids, xanthines, xanthones, and alkaloids, a review can be found in [1].

 

Natural

•             Geiparvarin

•             Desmethoxyyangonin, a constituent of kava extract; modest affinity

•             Catechin and epicatechin, poor affinity

•             Garlic

•             Rosiridin

 

Figure 2. Some natural MAO-B inhibitors from [1]

 

An Australian plant, Geijera parviflora, contains geiparvarin, a coumarin derivative in the leaves which inhibits MAO-B

 

Some simple small molecule MAO-B inhibitors include methyl piperate, a derivative of piperine from black pepper. Whilst there is some dispute on the MAO-A/B selectivity, one source claims it is more selective for, and relatively potent towards MAO-B [2].

 

Figure 3. Structure of methyl piperate

 

Recent research [3] identified ethyl ferulate as a novel neuroprotective MAO-B inhibitor, displaying greater affinity than rasagiline

 

Figure 4. Structure of ethyl ferulate

 

Ferulic acid is conveniently available pure in small and bulk quantities fairly cheaply and serves as a convenient material for the simple synthesis of ethyl ferulate via a Fisher esterification with ethanol [4].

 

Figure 5. Binding of ethyl ferulate to hMAO-B from [3]

 

“Ethyl ferulate could bind to the active site (substrate-binding site) of human MAO-B (hMAO-B) by hydrogen bound in a relative low binding energy (Binding energy = -6.47 kcal/mol

 

…analysis showed that ethyl  ferulate exhibited a higher affinity with hMAO-B than rasagiline mesylate, suggesting hMAO-B was a molecular target of ethyl ferulate.”

 

One benefit to ethyl ferulate is it is a lipophilic ester derivative of a well-studied molecule, also with it’s own beneficial properties. That said, being an ester, it is likely subject to extensive hydrolysis in the GI tract and on first pass metabolism, which could hinder it's use.

 

Ferulic acid is a phenolic compound that exhibits neuroprotective effects in the central nervous system [5, 6]. It has antidepressant properties by increasing the 5‐HT, NE, and DA levels in the synaptic cleft of frontal cortex and hippocampus via regulating the monoamine system. It also has antioxidant, anti-inflammatory and neurotrophic effects.

 

Ethyl ferulate

-novel natural compound that could be used for therapeutic purposes as a potent inducer of HO-1 for the protection of brain cells against oxidative and neurodegenerative conditions.

- Potently suppress microglia-mediated neuroinflammation by binding to MAO-B

 

Improving the properties of ferulates

 

Both the phenethyl ester and phenethylamide [7,8] of ferulic acid seem to have potent MAO-B inhibitory properties, the amide having the properties of resistance to hydrolysis in vivo by esterases

 

Figure 6. Ferulamides 

 

[1] Carradori, S., D’Ascenzio, M., Chimenti, P., Secci, D., & Bolasco, A. Selective MAO-B inhibitors: a lesson from natural products. Molecular Diversity, 18(1), 219–243. (2013) doi:10.1007/s11030-013-9490-6 

 

[2] Lee SA, Hwang JS, Han XH, Lee C, Lee MH, Choe SG, Hong SS, Lee D, Lee MK, Hwang BY. Methylpiperate derivatives from Piper longum and their inhibition of monoamine oxidase. Arch Pharm Res. (2008) Jun;31(6):679-83. doi: 10.1007/s12272-001-1212-7.

 

[3] Zou X, Gao S, Li J, Li C, Wu C, Cao X, Xia S, Shao P, Bao X, Yang H, Liu P, Xu Y. A monoamine oxidase B inhibitor ethyl ferulate suppresses microglia-mediated neuroinflammation and alleviates ischemic brain injury. Front Pharmacol. (2022) Oct 13;13:1004215. doi: 10.3389/fphar.2022.1004215.

 

[4] Esterification, Purification and Identification of Cinnamic Acid Esters

 

[5] Dong X, Zhao D. Ferulic acid as a therapeutic agent in depression: Evidence from preclinical studies. CNS Neurosci Ther. (2023) Sep;29(9):2397-2412. doi: 10.1111/cns.14265.

 

[6] Sgarbossa A, Giacomazza D, di Carlo M. Ferulic Acid: A Hope for Alzheimer's Disease Therapy from Plants. Nutrients. (2015) Jul 15;7(7):5764-82. doi: 10.3390/nu7075246.

 

[7] Badavath, V. N., Baysal, İ., Uçar, G., Mondal, S. K., Sinha, B. N., & Jayaprakash, V. (2015). Monoamine Oxidase Inhibitory Activity of Ferulic Acid Amides: Curcumin-Based Design and Synthesis. Archiv Der Pharmazie, 349(1), 9–19. doi:10.1002/ardp.201500317

 

[8] Koichi Takao, Kazuhiro Toda, Takayuki Saito, Yoshiaki Sugita, Synthesis of Amide and Ester Derivatives of Cinnamic Acid and Its Analogs: Evaluation of Their Free Radical Scavenging and Monoamine Oxidase and Cholinesterase Inhibitory Activities, Chemical and Pharmaceutical Bulletin, 2017, Volume 65, Issue 11, Pages 1020-1027, Released on J-STAGE November 01, 2017, Online ISSN 1347-5223, Print ISSN 0009-2363, https://doi.org/10.1248/cpb.c17-00416,

Edited Friday at 03:03 AM by Alchemica

[Darklight]

1 hour ago, Alchemica said:

 The activity of MAO-B is generally higher in patients affected by neurodegenerative diseases like Alzheimer's and Parkinson's, as such being used therapeutically, particularly in PD.

 

Legend. I did not know this. Have also been wondering lately why some compounds have more effect on ppl than others

 

Thanks mate, I must get back to your pdf page, this one's a complex read so it's good the rain's still going ❤️

[Starward]

@Alchemica What about Peganum harmala (Harmaline/Harmine)? A readily available, plant-derived MAO-B inhibitor

Edited March 7 by Starward

[Alchemica]

17 minutes ago, Starward said:

@Alchemica What about Peganum harmala (Harmaline/Harmine)?

Harmine is a high potency reversible inhibitor of MAO-A with specificity for the MAO-A isoform and does not, at most relevant doses, inhibit MAO-B. In general, both harmine and harmaline are considered reversible MAO-A inhibitors. Norharman is more selective for MAO-B

Samoylenko et al., 2010 and Wang et al., 2010 reported the inhibition of MAO-A and MAO-B by harmine, harmaline, and tetrahydroharmine. In that case, the selectivity for MAO-A for both alkaloids was much greater for MAO-A than the -B isoform, IC50 2.5 and 2.0 nM for MAO-A, and 25 and 20 μM for MAO-B, respectively. However, Wang et al., 2010 did not find any MAO-B inhibitory activity by the aforesaid alkaloids

[fyzygy]

Acacia baileyana (among others) is rumoured to have MAOI activity. Some research is on A. baileyana is mentioned in a footnote here: https://www.mdpi.com/2223-7747/11/23/3356

 

 

Edited March 7 by fyzygy