Tweaking With Harmine, And Family

[Morninggloryseed]

In the literature, there are not many harmine analogues that have been used in medicine...but there are a few.

Most seem to be Valium-like drugs, one is a serotonin antagonist and a couple reverse the effects of benzos, causing anxiety and panic states. Some have nootropic effects.

http://en.wikipedia.org/wiki/Category:Beta-Carbolines

But I would love to tweak harmine (or harmaline or THH) to improve its MAOI potency, perhaps also increasing its psychedelic potential....maybe finding an all-in-one ayahuasca pill.

Here are a few I came up with.

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[Morninggloryseed]

And some more

The last one is my favorite...if I had the means that would be the one I would explore first.

 

[TheAzo]

You must be very careful with taking something like that something which happened to act as both an MAOI and a releaser/reuptake inhibitor could be serotonin syndrome in a pill instead of ayahuasca in a pill.

Since it looks like you're taking a que from existing triple release agents, that's something to think hard about. Luckily, i think it's very unlikely that the SAR holds.

 

[Morninggloryseed]

Ok...one more. This is not found in nature. Why? I call it 'iso-harmine'

 

[Morninggloryseed]

I'd feed them to POWs first.

 

[TheAzo]

I'd feed them to POWs first.

Sounds good to me. Can I watch?

 

[Morninggloryseed]

Speculation is fun. Anyone wonder why seemingly so little has been done with beta-carbolines? Tryptoline, McIsaac's Compound, and others are found in the human brain and play a role in consciousness. The harmala alkaloids are known and effective anti-depressants.

It just seems odd to me that there are tens of hundreds of cannabinoids, thousands of active PEA and tryptamine psychedelics, dozens of semisynthetic compounds made from ibogaine and lysergic acid in the literature. So why so little interest in the beta-carboline family?

 

[Phener]

I know this may seem like going OFF topic but the key structure in Latrepirdine (ignoring the N-substitution part which makes it an antihistamine) looks an interesting starting molecule. (not too disimilar from harmine)

http://en.wikipedia.org/wiki/Latrepirdine

we do REALLY need to clone SHULGIN so he can write books on HIHKAL (harmolines I known and loved) amongst MANY more, such a shame everything is pushed so underground

 

[hamhurricane]

Speculation is fun. Anyone wonder why seemingly so little has been done with beta-carbolines? Tryptoline, McIsaac's Compound, and others are found in the human brain and play a role in consciousness. The harmala alkaloids are known and effective anti-depressants.

It just seems odd to me that there are tens of hundreds of cannabinoids, thousands of active PEA and tryptamine psychedelics, dozens of semisynthetic compounds made from ibogaine and lysergic acid in the literature. So why so little interest in the beta-carboline family?

well i think the basic answer to your question is:
1. betacarbolines (for the most part) have low affinity for 5HT2x receptors and usually dosages which are in the 100s of mg making custom syntheses impractical.
2. the subjective effects of betacarbolines are often nauseating/unpleasant and though psychedelic not "useful" therapeutically or recreationally.
3. there is some reason for concern regarding toxicity - especially purkinje cell toxicity
4. the 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (really surprised this does not have a trivial name!) backbone of ibogaine is very similar to a betacarboline and might be a better starting place for exploration.

none of this is to say they should not be explored, everything should be explored. i think 6-methoxylation would probs raise potency and from there who knows...

 

[hugo24]

Phener, there actually IS a Shulgin successor, think "Psychedelische Chemie"...

 

[Hammilton]

aren't a lot of these beta carbolines neurotoxic, though? That seems like a good reason to avoid them.

 

[Morninggloryseed]

Where does it say that?

 

[hamhurricane]

^^^
ahem...what i just said 8)

Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline

The Olivocerebellar Projection Mediates Ibogaine-Induced Degeneration of Purkinje Cells: A Model of Indirect, Trans-Synaptic Excitotoxicity

Central neurotoxic effects of intraperitoneally administered 3-acetylpyridine, harmaline and niacinamide in Sprague-Dawley and Long-Evans rats: A critical review of central 3-acetylpyridine neurotoxicity

also with regards to your proposed structures you are using common PEA substituents, although i have never seen the docking of beta-carbolines modeled i would imagine they bind to 5HT2a more like a tryptamine than a phenethylamine - for that reason i would first investigate 6-methoxylation (analogous to 5-MeOs on tryptamines) and then substitutions on the nitrogen to produce a tertiary amine. something as simple as 2-Me-Pinoline could be quite interesting, if only as an alternative MAOI.

Also, its interesting to note that tetrahydroharmine is simply cyclized 6-MeO-NiPT. Both mckenna and naranjo noted the auditory distortions produced by harmala alkaloids - perhaps THH has some (extremely minor) pharmacological overlap with 5-MeO-DiPT which produces undeniable auditory distortions at higher doses. for this reason i would love to explore cyclized DiPT and 5-MeO-DiPT (or NiP-THH) as possible conformationally constrained auditory hallucinogens.

 

[Nexus298]

I know this is off topic but where do yall get the software to draw molecules. and especially the ones you can over lay 2 different molecules?

 

[Morninggloryseed]

^^^
ahem...what i just said 8)

for this reason i would love to explore cyclized DiPT and 5-MeO-DiPT (or NiP-THH) as possible conformationally constrained auditory hallucinogens.

What a great idea!

 

[Hammilton]

there is a whole lot on the neurotoxicity of beta-carbolines.

Some are compared to mptp, IIRC.

http://www.google.com/#hl=en&source...yzASyxoD_CwAAAKoEBU_QlpA_&fp=250d288cd3d71764