Exploring endogenous neuroprotectants - 1MeTIQ

[Alchemica]

Exploring endogenous neuroprotectants - 1MeTIQ

While many tetrahydroisoquinolines display neurotoxic (salsolinol - 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline)/Parkinson's-inducing effects (1-Benzyl-TIQ), there are some that offer neuroprotection and are of potential merit therapeutically. 

 

These include 1MeTIQ (1-Methyl-1,2,3,4-tetrahydroisoquinoline) which has a plethora of beneficial effects on the CNS which has placed it in the category of being an 'endogenous neuroprotective agent'. That said, it's clinical utility may be limited by MAO-A and -B inhibition which opens up potential for pharmacodynamic interactions with other medications.

Nonetheless, the array of beneficial CNS actions of 1MeTIQ have led to research interest for both Parkinson's and as an anti-addictive agent.
 

1MeTIQ

 

Often these are synthesised in vivo by the Pictet-Spengler reaction with aldehydes or pyruvate with the corresponding amine, eg. dopamine and acetaldehyde for salsolinol. While formation of tetrahydro-β-carbolines is much more rapid, the non-indolic isoquinolines generally require more vigorous reaction conditions but still can form in vivo normally through enzymatic catalysis.

 

That said, reactions of unsubstituted arylethylamines can be difficult with variable results, reaction has long been limited to active substrates which bear strongly electron-donating groups such as a methoxy or a hydroxy group on the benzene ring.

 

Pictet-Spengler reaction 

Oxidation of the tetrahydro-β-carboline derivatives affords the β-carbolines 

 

A variety of Pictet-Spengler reaction products are formed in food during roasting, for example it is the reaction that leads to the majority of β-carbolines in coffee, for example norharman/harman. Sugars can also condense with the biogenic amines. These food derived β-carbolines become the predominate dietary source of MAO inhibiting substances

Other common condensation products include those from the aromatic amino acids eg. Trp and aldehydes, which in turn forms the 3-carboxylate. These tend to have GABAA BZD antagonistic/inverse agonistic properties in the β-carbolines ie. being convulsant

 

 

Other properties have been ascribed to the THBCs, namely inhibition of serotonin reuptake, and agonist affinity to 5-HT1A/2ARs. For the THIQ's, affinity to the serotonin receptors, including 5-HT7 has been noted.

 

Decarboxylation of TIQ-1-COOH's is more difficult but THBC-1-COOHs seem to be decarboxylated in MeOH/HCl with heating.

1MeTIQ:
- endogenous amine synthesised in human and animal brain
- exogenous 1MeTIQ has high affinity for brain tissue
- profoundly stimulates dopamine release
- 1MeTIQ expresses neuroprotective properties
 - 1MeTIQ demonstrates antiaddictive potency - considerable potential as a drug for combating substance abuse disease through the attenuation of craving.
- free radical scavenging properties 
- 1MeTIQ reversibly inhibits MAOA and MAOB: in vitro and in vivo studies
- 1MeTIQ is a partial dopamine agonist
- distinct antidepressant-like activity
- possesses mild activity at NMDA receptors.
- may be considered a potential agent useful in the treatment of the cognitive symptoms of schizophrenia. It has no neuroleptic like affinity for DA receptors, however, they interfere with the agonist binding to DA receptors, which suggests that the compounds may suppress excessive dopaminergic transmission at a site different from neuroleptic binding sites 
- Absence of 1MeTIQ toxicity, mutagenicity or carcinogenicity'

"This ability of 1MeTIQ may be of clinical importance and raises hope for its application in neurodegenerative diseases (e.g., Parkinson’s disease) and addiction evoked by drugs of abuse."

 

Two synthetic routes were proposed, the first being hindered by rapid formation of resinous condensation products and low yields of the copper (II) chelate.

Traditionally, the thermal decarboxylation of Cu (II) amino acid chelates is conducted in DMSO or high boiling point glycols but methylsulfonylmethane was selected as a polar solvent mp ~100 degrees.
 

 

Synthetic route 1.
 

Synthetic route 2.

 

Formation of the Cu (II)-Phe chelate was much more quantitative.

 

To validate the Pictet-Spengler reaction and subsequent decarboxylation with a biogenic amine, equimolar quantities of amine, calcium pyruvate and excess H3PO4 were heated in EtOH. After reacting, the insoluble calcium phosphate removed and ethanolic solution reduced.

This reaction was followed by TLC, A - the starting amine showed complete disappearance in B, being replaced by a new fluorescent high Rf compound. Absence of solubility in alkaline solutions confirmed the loss of the carboxylate.

 

  

References
Herraiz T, Chaparro C. Human monoamine oxidase enzyme inhibition by coffee and beta-carbolines norharman and harman isolated from coffee. Life Sci. 2006 Jan 18;78(8):795-802. doi: 10.1016/j.lfs.2005.05.074. Epub 2005 Aug 31. PMID: 16139309.
Antkiewicz-Michaluk L, Wąsik A, Michaluk J. 1-Methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous amine with unexpected mechanism of action: new vistas of therapeutic application. Neurotox Res. 2014 Jan;25(1):1-12. doi: 10.1007/s12640-013-9402-7. Epub 2013 May 30. PMID: 23719903; PMCID: PMC3889699.
Antkiewicz-Michaluk L, Filip M, Michaluk J, Romańska I, Przegaliński E, Vetulani J. An endogenous neuroprotectant substance, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), prevents the behavioral and neurochemical effects of cocaine reinstatement in drug-dependent rats. J Neural Transm (Vienna). 2007 Mar;114(3):307-17. doi: 10.1007/s00702-006-0546-y
Antkiewicz-Michaluk L, Romańska I, Wąsik A, Michaluk J. Antidepressant-Like Effect of the Endogenous Neuroprotective Amine, 1MeTIQ in Clonidine-Induced Depression: Behavioral and Neurochemical Studies in Rats. Neurotox Res. 2017 Jul;32(1):94-106. doi: 10.1007/s12640-017-9715-z.
Wąsik A, Możdżeń E, Michaluk J, Romańska I, Antkiewicz-Michaluk L. 1-Methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous Neuroprotectant and MAO inhibitor with antidepressant-like properties in the rat. Neurotox Res. 2014 May;25(4):323-34. doi: 10.1007/s12640-013-9425-0.
Mozdzen, E., Babinska, I., Wójcikowski, J., & Antkiewicz Michaluk, L. (2019). 1-Methyl-1,2,3,4-tetrahydroisoquinoline - the toxicological research on an exo/endogenous amine with antidepressant-like activity - in vivo, in vitro and in silico studies. Pharmacological Reports. doi:10.1016/j.pharep.2019.06.016
Ishiwata, K., Koyanagi, Y., Saitoh, T. et al. Effects of single and repeated administration of 1,2,3,4-tetrahydroisoquinoline analogs on the binding of [11C]raclopride to dopamine D2 receptors in the mouse brain. J Neural Transm 108, 1111–1125 (2001). doi:10.1007/s007020170001

Edited March 5, 2025 by Alchemica

[Breizh]

It seems that using phenethylamine and acetaldehyde might offer a simpler approach.

[Alchemica]

True but acetaldehyde is often more troublesome to obtain/synthesise, calcium pyruvate is a cheap bulk nutritional supplement here

 

Came to the conclusion unsubstituted PEAs aren't great Pictet-Spengler substrates many a time (unlike 3,4-OH/MeO etc which are much more effective) and require much stronger reaction conditions, often instead preferring the Bischler-Napieralski Reaction .

[Breizh]

I found this paper earlier, it's about tetrahydroisoquinolines with neuroprotective and neurorestorative properties:

 

> Remarkably, recent findings suggest that some TIQs such as (1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol) (higenamine) and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) as well as N-methyl-tetrahydroisoquinoline (N-methyl-TIQ) exert unique neuroprotective and neurorestorative actions. The present review article provides an overview on these aspects of TIQs and summarizes those that presently appear the most significant highlights on this puzzling topic.

 

https://doi.org/10.1007/s12640-019-00051-9

Edited March 6 by Breizh