What's the strongest Cholinergic Drug ?

[MedicinalUser247]

Structure activity relationship for cholinergic drugs​

1. A molecule must possess a nitrogen atom capable of bearing a positive charge, preferably a quaternary ammonium salt.
2. For maximum potency, the size of the alkyl groups substituted on the nitrogen should not exceed the size of a methyl group.
3. The molecule should have an oxygen atom, preferably an ester-like oxygen capable of participating in a hydrogen bond.
4. A two-carbon unit should occur between the oxygen atom and the nitrogen atom.
5. There must be two methyl groups on the nitrogen.
6. A larger third alkyl group is tolerated, but more than one large alkyl groups leads to loss of activity.
7. The overall size of the molecule cannot be altered much. Bigger molecules have poorer activity.

So, What's the strongest Cholinergic Drug ?

 

[TheLightBringer]

Probably some kind of chemical weapon like Sarin or VX. Theyre both super potent acetylcholenisterase inhibitors, not something id ever dare to be in the same room as.

 

[MedicinalUser247]

I'm looking for the strongest Cholinergic that will get you High. Right now I'm researching Cholinergics.

 

[TheLightBringer]

I'm looking for the strongest Cholinergic that will get you High. Right now I'm researching Cholinergics.

Well no typical cholinergics will get you ”high” in the sense that theyll cause intense euphoria and altered states. I guess nicotinic acetylcholinergic and muscarinic compounds will but the amount of recreational cholinergics are few.

Nicotine and Arecoline are pretty much as good as it gets bar some obscure derivatives of them that have no human data.

If youre looking for cognitive enhancement then id say Donepezil is pretty top of the line. Just be aware if you have predisposition to OCD/rumination then donepezil will amplify it to an extreme degree (as will other potent AChe inhibitors)

 

[emkee_reinvented]

I'm looking for the strongest Cholinergic that will get you High. Right now I'm researching Cholinergics.

Might be better to train your self to have hypnagogic dream s they are kinda like that without having to take a Cholinergic. And they stimulate creativity, not that i advise it though they were horrible but they came unwanted.

There are people doing that and although it seem s a lot safer. It s not 100 5 ime. Maybe have tripsitter in either case.

 

[Skorpio]

You ever get nicotine poisoning? That’s a good example of strong cholinergic effects.

For a direct cholinergic agonist, may I suggest epibatidine, a potent chlorinated natural product that was recently in the news for its use as a poison by Putin. This compound is strongly analgesic, and drug companies tried to develop it back in the day into something that was less toxic, to make a non-opioid analgesic. No analog developed ever had mild enough side effects to get approved.

Or maybe you wanna get more nonselective and into the realm of acetylcholinesterase inhibitors. Then you get some of the really nasty stuff like EA-4056, a carbamate nerve gas that is 3 times more potent than VX.

For actually taking, I’d echo TheLightBringer and say best bets are things like nicotine or arecoline or very weak acetylcholinesterase inhibitors.

 

[Deleted member 170540]

Here's a patent describing the use of acetylcholinesterase inhibitor alkaloid huperzine A mixed with amino acids to improve blood growth hormone levels

US20040110783A1 - Compositions and methods for increasing growth hormone levels - Google Patents

A composition for increasing GH levels in a mammal including effective amounts of huperzine A and secretagogue amino acids and methods thereof.

patents.google.com

Huperzine A also binds to NMDA receptors, which is why there are attempts to produce some synthetic derivative for use as a neuroprotective drug.

The organophosphate nerve agents are dangerous because most of them evaporate enough at ambient temperatures to cause harm at longer distance if spilled somewhere, unlike epibatidine or EA-4056 which would have to be deliberately disseminated as dust particles if someone or a nation were to use them as a weapon. And the organophosphates can also cause neurological damage (Gulf war syndrome?) at lower exposure levels that don't show up as immediate acute toxicity.

 

[Smyth2]

You ever get nicotine poisoning? That’s a good example of strong cholinergic effects.

For a direct cholinergic agonist, may I suggest epibatidine, a potent chlorinated natural product that was recently in the news for its use as a poison by Putin. This compound is strongly analgesic, and drug companies tried to develop it back in the day into something that was less toxic, to make a non-opioid analgesic. No analog developed ever had mild enough side effects to get approved.

Or maybe you wanna get more nonselective and into the realm of acetylcholinesterase inhibitors. Then you get some of the really nasty stuff like EA-4056, a carbamate nerve gas that is 3 times more potent than VX.

For actually taking, I’d echo TheLightBringer and say best bets are things like nicotine or arecoline or very weak acetylcholinesterase inhibitors.

Current work is on a compound called Ropanicant that is in clinical trials.

 

[TheLightBringer]

Here's a patent describing the use of acetylcholinesterase inhibitor alkaloid huperzine A mixed with amino acids to improve blood growth hormone levels

US20040110783A1 - Compositions and methods for increasing growth hormone levels - Google Patents

A composition for increasing GH levels in a mammal including effective amounts of huperzine A and secretagogue amino acids and methods thereof.

patents.google.com

Huperzine A also binds to NMDA receptors, which is why there are attempts to produce some synthetic derivative for use as a neuroprotective drug.

Huperzine A is quite potent compared to others, I thought of mentioning it but it pales in strength to some others and doesnt have any recreational use. I was taking 800ug - 1mg of it daily for a period of time when combining it with MK-677 and peptides to inhibit somatostatin and maximize GH release. Cant say I ”felt” much regarding cholinergic effects though, it definetly worked as far as cognitive enhancement but something like Donepezil will beat it ime.

 

[Smyth2]

I bought Huperzine A a couple of times in the past and can't say that it did anything for me.

 

[Deleted member 170540]

Muscarinic M4 receptors inhibit dopamine release in the reward circuitry, while M5 receptors increase dopamine release. If someone were to take a small dose of an anticholinergic that binds to M4 but not M5, and combine it with huperzine A, then that would preferentially activate M5 receptors and theoretically cause a mood elevating effect. But that would be more for improving your baseline mood than for getting "high".

 

[4DQSAR]

A quaternary amine will mean a ligand cannot cross the BBB. So do you mean a periperal ligand?

 

[Deleted member 170540]

A quaternary amine will mean a ligand cannot cross the BBB. So do you mean a periperal ligand?

If you mean the quaternary acetylcholinesterase inhibitor mentioned by Skorpio, it probably doesn't cause convulsions which are a CNS nicotinic effect, but still paralyzes muscles as excess acetylcholine in the neuromuscular junction acts as a depolarizing muscle relaxant. And that type of compounds probably also constrict airways if inhaled, slow pulse down enough to make physical excercise difficult and impair vision by affecting accommodation.

 

[4DQSAR]

No, not specifically. The most potent nerve agents I'm aware of were those developed at Edgewood Arsenal and of those it was an aryl carbamate rather than a phosphamate (or related +5 P species) that was central to their activity.

That they contained quaternary ammonium moieties may well also have increased that affinity at the cost of them not crossing the BBB.

After all, it's blockade of the peripheral receptors that kills.

 

[Smyth2]

When i was at uni, tebanicline was the drug in clinical development.

Another design is related to bicifadine and amitifadine but with a pyridyl aromatic ring instead: [919106-12-0].

Phil Skolnick & Zhengming Chen, WO2008153937 (to Ethismos Research Inc, DOV Pharmaceutical Inc).

 

[4DQSAR]

I seem to recall that one was derived from a toxin found in South American 'poison dart' frogs. There was quite a stir because nobody imagined aryl chlorides occured in nature. Didn't they discover that the frogs didn't produce it but rather it was something in their diet?

Has anyone worked out what bug(s) in the frog's diet were actually producing the aryl chloride? Last time I searched, I couldn't find any later work that specified the species responsible.

 

[Deleted member 170540]

I seem to recall that one was derived from a toxin found in South American 'poison dart' frogs. There was quite a stir because nobody imagined aryl chlorides occured in nature. Didn't they discover that the frogs didn't produce it but rather it was something in their diet?

Has anyone worked out what bug(s) in the frog's diet were actually producing the aryl chloride? Last time I searched, I couldn't find any later work that specified the species responsible.

I find it even more surprising that thyroid hormones have three iodine atoms on aromatic rings. Maybe a chlorine version also forms in trace amounts in the thyroid of some animal species.

 

[Smyth2]

I seem to recall that one was derived from a toxin found in South American 'poison dart' frogs. There was quite a stir because nobody imagined aryl chlorides occured in nature. Didn't they discover that the frogs didn't produce it but rather it was something in their diet?

Has anyone worked out what bug(s) in the frog's diet were actually producing the aryl chloride? Last time I searched, I couldn't find any later work that specified the species responsible.

John Daly found that the frogs only produced traces of epibatidine if the frogs were raised on the cacao plantations and not on the banana plantations.

 

[4DQSAR]

John Daly found that the frogs only produced traces of epibatidine if the frogs were raised on the cacao plantations and not on the banana plantations.

Well, that DOES narrow things down somewhat.

Like the idiot I am I wrote stating the source of epibatidine was unknown only to discover a paper demonstrating that the american cockroach (Periplaneta americana L.) contain traces in their nerve cord it albeit in tiny amounts. So I guess it's possible that something could concentrate it and the frogs consume whatever the thing is.

@polymath - Aryl iodides and aryl bromides both turn up in odd places. We know of that bromoperoxidase and iodoperoxidase do the heavy lifting. A Fungus (Caldariomyces fumago L.) commonly known as sooty mold have been shown to containe chloroperoxidase AND is known to grown in the regions where the frogs were discovered. Aphids spread it so I suppose that taken with @Smyth2 noting where epibatidine is and is not found might give us insight. Aphids may not take to a diet of cocao? But that's purely a hypothesis. The 'exciting' bit would be getting the funding to test said hypothesis. Sadly, since no use for epibatidine is known, funding could be tough and you may discover the hypothesis to be wrong.

But here we are - what none of us can do alone, together we can figure it out. Cool!