• N&PD Moderators: Skorpio | thegreenhand

  • Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

Theoretically longest lasting drug (some super agonists or?)

I know it might be just be me fantasising but what I wonder in fact is how much duration of drugs can be prolonged before lasting effect drugs doesn’t become by mechanism of neurotoxicity. In fact what would be best is if a long lasting drug would in fact have neuroprotective effects along long lasting high.
 
SpiralusSancti said:
After-glow of dissos also can last quite a bit.
Click to expand...
Definitely, I've had dissociation and hypomania for weeks after a 3-MeO-PCP binge. My guess is that this is mostly due to partitioning into fat tissue, since the more water soluble dissociatives like MXE never had aftereffects that long, even after heavy binges. The other possibility (especially with the hypomania) is that changes in gene expression are sustaining these effects. Someone make a neutralizing antibody for 3-MeO-PCP and we can test this for sure. :ROFLMAO:

@Kaleida had a heavy exploration of 5-MeO-tryptamines that had very strong aftereffects after ceasing usage that could probably be explained by changes in gene expression. Especially with 5-HT2A agonists, the changes in gene expression are intrinsic to the 5-HT2A expressing pyramidal neurons. The function of these neurons is initially modulated by the activation of the 5-HT2A receptor, but the downstream changes in gene expression within these neurons might sustain functional changes even following drug clearance.

Epigenetic exceptions and cases of covalent/irreversible modulation aside, half-life is probably going to set the theoretical upper limit of duration, because noncovalent interactions generally occur on shorter timescales. The average lifetime of one of these noncovalent interactions is just the inverse of the dissociation rate, and even for a high affinity drugs like carfentanil this only comes out to about 5.5 minutes. LSD has the slowest dissociation rate of any drug I'm aware of (average lifetime of LSD-5-HT2A complex is like 220 minutes), which still isn't close to things like flubromazepam (half-life 100+ hrs and even normal dose had me high for like an entire week).
 
Last edited:
˄that’s what I’m talking about!!!

something-HT2A complexes are still vastly unexplored, as in hundreds, possibly thousand of substances tested in humans are still unexplored in a such a way as LSD is, so we can expect new recorders in that aspect

creating substance that dissolves in fat so fine that it can me injected into fat tissue directly and still create ER is possible. simplest would be with a substance that is liquid and room/body temp and potent enough
 
The problem with such long duration is that often it's not ideal for practical usage. I HAVE suggested that (R) DOM might well be better than the racemate. If one has the nitropropene to hand, it's a simple matter to produce the ring-substituted PMK and then one can use a chiral auxiliary to yield 100% (R). It's a bit more work, but you get twice as much product.

I might also add that said chiral auxiliary is a liquid at RT and so is much more practical to handle. DOM is one of the few things it's practical to make in the kitchen since it's so potent. And having seen the prices people will pay for LSD derivatives, a 2.5mg blotter selling for £10 would be £4 million.

OK so you would have to wholesale but at £2 a blotter, one could make £50K of the stuff at a time.

I might add that I haven't given anyone a specific route nor named any specific compounds. It's interesting, but it's also illegal and I don't DO illegal.

The law doesn't cover the hydroxylamine OR the N-formamides but both are converted to the amine within the body. STILL controlled in the UK but one can protect the amine in such a way that it would need to be boiled in water for 1 hour. That way I am selling an inactive compound, the BUYER is then converting it into the active.
 
BTW 'super agonist' does not mean 'more potent' or 'longer lasting'. It's a technical term much beloved by real researchers and wanna-be drug king-pins.
 
ibb.co

1 hosted at ImgBB

Image 1 hosted in ImgBB
ibb.co ibb.co

The above is some x200 Δ9-THC (according to a Greek medicinal chemist - you will have to find the name) and has a T1/2 of just over 600 hours. As far as I can tell, physically (as - 'in the petri-dish' & and 'the hit when you smoke in a bowl') it's more or less indistinguishable from normal honey oil with which it freely mixes.

The KEY difference is that the cyclobutyl (bond-angles explain why cyclobutyl is so good) makes it a super-agonist (i.e. it activates cells more than the bodies natural transmitter) and the fact that it lasts for 6-7 weeks.

I PRESUME that people who smoke dope morning noon and night wouldn't really notice a change. You would ONLY know that it was different if and when you stopped using dope. I suspect that after the first month you would just adjust (as the constantly stoned do) so it wouldn't be THAT scary. You would simply have to accept that you would be stoned for the rest of your life.. and their are worse things.

My wife brought me back some chocolate cake from Amsterdam and it was subtle but lasted for 12 hours. Didn't seem to affect my life in any negative manner and so I wouldn't mind one a day.

But of course, if you hit the oil-pipe to REALLY listen to your Pink Floyd and Greatful Dead albums in full detail, it might be disconcerting. Imagine that after a Friday night sesh you are just as stoned the following Thursday.... and the following Thursday.... and the following Thursday....

I PRESUME it was developed as a chemical weapon (papers are 79-83) because it's so potent that a fine mist of it would work. It would make for docile, compliant and non-aggressive workers. Of course, those with a predisposition to schizophrenia may not react well since the disease amplifies everything. I don't fear VX gas, I fear this (It's more potent than VX). I mean, since it won't show up on most tests, how do we know it's not 'standard issue'?

BTW Neuroleptics will not help. So maybe we are a generation of people all living stoned lives? I am almost certain that my memory used to be much better (but I forget) but then nothing much bothers me any more. I'm of the so-so generation.

How would we know? I just don't let it worry me...

But it isn't the MOST potent by a large margin. I know of some compounds over 18000 Δ9-THC BUT they are more easily detected. IF I sought to make an untraceable social-control drug, it would be something like this,

Super-agonism has nothing to do with super-potency per se. I know benzos less potent than diclazepam that are technically super-agonists but I didn't go with them because they are a 1 way street. When the body becomes used to something that sends a stronger signal, after a few months it can never recover...

That is why I'm not happy, but not outright alarmed by flunitrazolam. It's BAD, but it's an order of magnitude less than the WORST. Same with fentanyl. It's BAD, but their are super-agonists and if those were common, it would, in essence, make someone hooked for life (but maybe not a long time). They aren't even chemically complex. The term is simply derived from scientists discovering compounds that produced a response over and above the receptor's natural trigger....

Now a mixed benzo/opioid super-agonist - I presume some evil people seek it... but I'm not about to give them millions of souls and the $ billions associated with them, am I? I prefer to play the 'how potent can we make this REALLY simple compound'. As it is, I've got 11.5x M from a compound that costs $2500/Kg in precursors. Not THAT is useful. In a nation with few resources, an analgesic like hydroM that costs 1/10th the price has it's place...
 
I’m a person that would sometimes really enjoyed and even benefit (sometimes hugely) from a substance that makes me stoned for a month. I can think of many occasions where this would make for a perfect choice.

As for DOM. Well if substance is made so you have to boil it for an hour and inactive when just taken as it is, in that case I can’t really think rationale behind which it could be illegal even in UK (given it’s not made in UK from psychoactive substance). But importing and selling such substances in a form of some art, like using it on painting, nicely grown colored crystals, sealed in can that’s not to be opened (can called merde di politica)…

I know super-agonists doesn’t mean super strong. And understand what it means. What I’m not sure is, if a substance is super agonist it doesn’t have to also be irreversible agonist, right? So it can be super and irreversible, super and reversible or irreversible but not super?

I wast just assuming that those theoretically longest lasting drugs (both made and as an idea) would probably need to be irreversible super agonists to beat the record, or that doesn’t need to be a case?
 
I understand that, so there is no correlation between super agonists and irreversible agonists, right?

And would in fact super agonist that is also irreversible in theory be longest lasting drug of many groups? (not counting something that’s so liphophilic and potent that would be active upon excreting from fat tissue – like if THC metabolites stored in fact would be insanely potent; and not counting antagonists, releasers and blockers)
Is any substance known that is irreversible super agonist but not neurotoxic along that?
Is it possible to displace irreversible agonists even theoretically? If I’m understanding it correctly when such substance exists (that displaces irreversible agonist) that simply proves that something isn’t irreversible agonist.
 
Well irreversible agonists will bind and never unbind so given enough, they will reach 100% receptor occupancy which will tend to make them more potent and longer acting... chloroxymorphamine is actually x22M &it's duration is >48 hours, but it kill the receptor.

Carefully note that irreversible derivatives of both naloxone and buprenorphine have been tested. As have irreversible variants of the fentanyl class (normally have CFIT in the code-name).

It becomes questionable as to the specific action of compounds such as 2,5-dimethoxy-4-chloromethyl amphetamine (ClDOM) because they are listed as being far more active than their parent drug (in this case DOM) but they are also alkylating agents i.e. they bond irreversibly. Now that's something that the chaps at Клетка might well be looking into. Since it binds irreversibly, it wouldn't be detected in plasma....

And an undetectable analogue of DOM that might last for weeks would be an interesting way to ensure those out of favour wind up in a secure psychiatric unit for life or years (which ever is the shorter).

Drugs are morally neutral, but unless you are willing to accept how others might use them for evil purposes, it's nor moral to just put stuff 'out there'.
 
Last edited:
Good reasoning. Substances like that are surely best kept within very small circles.

As for using ClDOM or similar substance I’m positive they already did some (a lot?) work, as in putting people to psychic wards. But shouldn’t action of a such drug stop mostly by administration of antipsychotics? As even while LSD is still “docked” it’s action will mostly stop after administration of suitable antypsichotic.

I’m bet something that works on nicotinic receptors would work great for that too without worry that antipsychotics will be of much use. And it wouldn’t need to be really undetectable but could be made so only detectable metabolite is cotine.

I’m really picky when it comes to what’s good for others compared to what’s good for me and have no interest in compounds lasting for weeks except for myself.

When it comes to more alluring stuff (as in, more suitable for general public) things get really complicated as, sure, drugs are neutral in a sense but some carry, not only stigma, but somehow genuine momentum further from good or closer to good. I remember when I as a teen thought about smell of H as a smell of death. It’s a nice smell but very early I saw what it can do and to this day only met a few persons who can dance macabre dance with it just for a night, just for a month and not till death or worse stops it.

But there’s aspect of good even to deadliest drugs, aspect that’s rarely brought to light by average greed fuelled man. Think about fent. Basically the worst of worse in current drug world and still if it was done without $$ in eyes it would from beginning selling it in a form of JW for smokers and I.V. users, there wouldn’t be no dirty 30s but only blotters with printed potency in mics on every, there wouldn’t be flash eating cuts in it etc. And a step further would be abolishing it for analogue with a much higher TI. But there aren’t many people willing to play with monsters.
 
AlsoTapered said:
irreversible agonists
Click to expand...
An irreversible agonist is a type of agonist that binds permanently to a receptor in such a manner that the receptor is permanently activated. It is distinct from a mere (reversible) agonist in that the association of an agonist to a receptor is reversible, whereas the binding of an irreversible agonist to a receptor is, at least in theory, irreversible. Oxymorphazone is an example of an irreversible agonist. In practice, the distinction may be more a matter of degree, in which the binding affinity of an irreversible agonist is some orders of magnitude greater than that of an agonist.
@AlsoTapered Chloroxymorphamine is an opioid and a derivative of oxymorphone which binds irreversibly as an agonist to the μ-opioid receptor.
 
No - it's permanently BOUND. Look at naloxazone. One could easily produce the same analogue of diprenorphine which is a silent agonist. The latter doesn't DO anything except to blockade the receptor.
 
Wow. Found this thread a genuinely fascinating read.

Apologies in advance if I'm asking a stupid question.

So what happens physiologically as a result of a dose of oxymorphazone or chloroxymorphamine? The receptors are all permanently blocked and does this cause death in the subject or some kind of severe dysfunction?
 
From my understanding and @AlsoTapered is such more well versed in this field of science, but there is a process by which it rebuilds the receptors thus the covalent bond stays but the whole receptor get replaced.... I don't know the mechanism nor have time to study and read it to explain it to you.
start here

Irreversible antagonists covalently bind to the receptor target and, in general, cannot be removed.
 
There's people that know more about this than me but I think some MAOIs are irreversible agonists (Or antagonists, I forget which)...I don't know if that permanently changes you or not.

DIAZEPAM. It supposedly stays in your system for 6 weeks after you stop taking it, but it took OVER THREE MONTHS for me to stop testing positive for it in urine tests.

Phenobarbital for SOME people. It's half-life is anywhere from 2 hours to 72 hours.

I cold turkey'd methadone once and it took 10 days before I actually felt any real withdrawal from it (note: I was drinking heavily which may have hidden some of the wd) but then TEN FUCKING WEEKS of severe, acute withdrawal.
 
Delmonte421 said:
From my understanding and @AlsoTapered is such more well versed in this field of science, but there is a process by which it rebuilds the receptors thus the covalent bond stays but the whole receptor get replaced.... I don't know the mechanism nor have time to study and read it to explain it to you.
start here

Irreversible antagonists covalently bind to the receptor target and, in general, cannot be removed.
Click to expand...

^I think this is what I was referring to with the MAOI thing?
 
irreversible MAOI will either block MAO B or MAO A or both until same aren’t “recycled” while reversible will block MAO B or MAO A or both for X time and after that same MAO continues business as usual
 
it’s pretty much the same principle with any receptors, enzymes or whatever. If some substance is irreversible it stays where it docks until that receptor or enzyme isn’t at an end of lifetime and new ones are build
 
Delmonte421 said:
From my understanding and @AlsoTapered is such more well versed in this field of science, but there is a process by which it rebuilds the receptors thus the covalent bond stays but the whole receptor get replaced.... I don't know the mechanism nor have time to study and read it to explain it to you.
start here

Irreversible antagonists covalently bind to the receptor target and, in general, cannot be removed.
Click to expand...
Thankyou. I didn't even know that happened. Some reading for for me there, cheers.
 
You must log in or register to reply here.
Top