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Theoretically longest lasting drug (some super agonists or?)

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SpiralusSancti

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What would be basic guidelines in designing drug with effects that last for weeks or months or longer? I’m not thinking about delivery system but drug that ingested orally or nasally. And I’m not thinking about drug with longest half-life but about drug, while I know that there’s a strong coleration but that isn’t an absolute measure. I know that how liphofilic drug is also has some coleration but again isn’t an absolute measure. Than I wonder about super agonist? I suspect that even if drug is a super agonist isn’t necessary going to produce high lasting as long as new receptors don’t appear or I’m wrong? I come to that conclusion cuz even drugs that build up on receptors and with time cover all receptors like SSRI or anti-psychotics in reality stop working if person stops taking them possibly even after just skipping one dose. MAOIs on the other hand seem to retain effects for longer. But again I’m not so much interested in psychiatric medicine but in theoretically longest lasting recreational drug. I had taken a few drugs that had insanely long after-effects but longest high I experienced was from DOC and DOI and longest consistent peak probably with BDF. Longest high I experienced with opiates was with methadone. But I’m sure it’s possible to create drug that even in normal dose lasts for a week or longer, right? Reason why such drugs aren’t created is probably as most people would see such a long duration as a bad thing but I’m sure there’s a lot of people like me who would really enjoy something like that for travels and such occasion. I don’t count drugs that could theoretically last for an insane duration if taken in huge dose and stayed safe because of high TI, I’m only interested in something that would have a really long duration even in low doses and wonder what mechanism would be needed to create such substance.
 
I wonder, is there such thing as an irreversible agonist on neurological receptors? Similar to an irreversible enzyme inhibitor.

I suppose such a thing would be immensely neurotoxic... :unsure:
 
There are some research compounds that irreversible bind to the receptor. They are technically superagonists, but since they are ONLY used in research, safe to say they are toxic.

But the acetyl ester of R-4066 is x212 morphine and a T1/2 of 38 hours. Hence it being possible to give to clients 3 times a week.

In other classes e.g. benzodiazepines their are also superagonists. But they are going to lead to a position where the body can NEVER readjust to their absence.

It's just lucky that the people making flunitrazolam don't know of them, because ark my words, they WOULD make them to ensure as many dependent buyers as possible...
 
Resiniferatoxin is an example of a TRPV1 agonist that binds irreversibly, and yes it is selectively neurotoxic.

-GC
 
G_Chem said:
Resiniferatoxin is an example of a TRPV1 agonist that binds irreversibly, and yes it is selectively neurotoxic.

-GC
Click to expand...
Holy crap that stuff sounds scary. 16 billion scoville units 🔥. Severe pain in sub micrograms. Wow.

"At 16 billion Scoville units, resiniferatoxin is rather toxic and can inflict chemical burns in minute quantities. The primary action of resiniferatoxin is to activate sensory neurons responsible for the perception of pain. It is currently the most potent TRPV1 agonist known, with ~500x higher binding affinity for TRPV1 than capsaicin, the active ingredient in hot chili peppers such as those produced by Capsicum annuum. For rats, LD50 through oral ingestion is 148.1 mg/kg.[12] It causes severe burning pain in sub-microgram (less than 1/1,000,000th of a gram) quantities when ingested orally."
 
G_Chem said:
Resiniferatoxin is an example of a TRPV1 agonist that binds irreversibly, and yes it is selectively neurotoxic.

-GC
Click to expand...

Ever noted how many different medical conditions it was trialled for the treatment of?

Be REALLY careful because usually behind such a compound is a company in dire need of a cash-cow. If they put ALL of their chips on 1 compound, bad luck.

I've worked in drug discovery and 7 out of 10 candidates fail during animal studies, the rest... well 9 out of 10 of those will fail in human trials.

Small start-up are risky and knowing the venture capital people, they expect 9 out of 10 to fail! And that's with experts who REALLY look into the development and important related details such as patents.

If it's natural, you can only patent the usage. Even then you either make the patent narrow but strong, or broader but weaker....

The recent patent on tryptamines is weak. I could find an example with a specific use and STILL be able to get another patent. OK I may have to pay the people with the broad patent some... but that was the point of the tryptamine patent. To cash in on ANY drug their massive library covered.

Me, I've patented 3 compounds at MOST but if they are used, I can firmly state that I got there first.
 
Snafu in the Void said:
Holy crap that stuff sounds scary. 16 billion scoville units 🔥. Severe pain in sub micrograms. Wow.

"At 16 billion Scoville units, resiniferatoxin is rather toxic and can inflict chemical burns in minute quantities. The primary action of resiniferatoxin is to activate sensory neurons responsible for the perception of pain. It is currently the most potent TRPV1 agonist known, with ~500x higher binding affinity for TRPV1 than capsaicin, the active ingredient in hot chili peppers such as those produced by Capsicum annuum. For rats, LD50 through oral ingestion is 148.1 mg/kg.[12] It causes severe burning pain in sub-microgram (less than 1/1,000,000th of a gram) quantities when ingested orally."
Click to expand...

Yup, it’s also found in Euphorbia Honey. I’ve experienced Resiniferatoxin. In the honey it’s not a strong burn but you feel it mostly in the back of the throat (lots of TRPV1 there?) and it lasts for hours. Thankfully the analgesic/sedating aspect of the honey usually puts me out in an hour or so.

It’s got a pretty decent effect (the honey) but the comedown makes me feel like I just did a night full of cocaine or something. The high isn’t worth the next day feel.

-GC
 
What makes DOx chemicals last so long? Their half-life isn’t nearly as long as it might be expected for substances that can last for days in non-OD dose. Kinda like with LSD but I’m not sure about that as it’s showed that in fact LSD stays bind to receptors strong and long.

It’s also interesting that tolerance to Dox doesn’t last very long at all, not longer than to LSD and maybe even a less longer.

Would it be possible to make DOx like chemical that acts purely as stimulant and still lasts very long? That obviously wouldn’t be a good stuff expect maybe for combat or other few situations where staying up for days is necessary.

Is it possible that part of reason DOx last so long is, in sense mental and not purely neuropharamlogical? Like a ball start rolling when you start tripping and it lasts longer if trip gets stronger and it’s not completely dependant on how long substance sticks to receptors? I’m wondering that cuz myself and other people I know who took DOx in same doses had trips similar in quality (as in DOC was more calm for everyone while DOI more stimulating and so on) while at same dose some had hardly any effects after “just” 18h while others were tripping on same dose after two days. Ofc difference in brain chemistry plays major part in that but could part of it be also psychological? And it’s interesting that with LSD or shrooms or most other chemicals difference in duration of trip is never like with Dox. Never met anyone who had 2 – 3x longer experince with other chems while with DOx it’s really variable. With BDF (a lot smaller sample of people) it seemed everyone had about the same duration of trip so I don’t think difference in duration of trip can’t be explained simply with notion that if substance last for a long time it’s normal to also expect bigger difference in duration of experience.

I what direction it could be possible to modify DOx to make it even longer lasting? I can see something with mellow effects as DOC or mescaline that lasts for a long time and provides a healing experience that couldn’t be achieved in short trip while still not being dangerous as people I know who had experience on DOC on a big dose that lasted for days were able to sleep and woke up two times or even four times before getting back to baseline so I don’t think psychosis from not sleeping would be a problem if substance is mellow and relaxing.
 
According to Wikipedia bromo-dragonfly can last two or three days following one large oral dose.

Phenazepam (and it's metabolites) have a very long half life.

Memantine has a very long half life. It's easy to trip for a couple days on Memantine.
 
Yeah BDF definitely can last that long but with dose about 1mg most of the effects are gone within less than 24h, at least for me and people I know who tried it. I don’t remember if I had stronger or weaker isomer as that might influence duration of trip too.
 
There is a thread in this section detailing the difference between a drugs effects and its half life. I found it interesting that a drug effect can be felt less than it's half life or even more. Gabapentin has a 5 hour half life (at least in the literature for now) yet the effects can last 10-15 hours for me. Diazepam has a long half life but not comparable to its effects.

Yeah, what is the longest lasting drug? Maybe some of the antipsychotics?

My God the thought of a permanent benzo or opiate is scary. Thankfully our bodies work to balance.
 
l-deprenyl lasted for me a long time after last dose. After-glow of dissos also can last quite a bit. And I had very, very long after-effects from Datura.

But I’m wondering about drugs that have very long duration in a sense of real high as otherwise I could say psychedelics last for longest time as I had more than one trip that I could definitely say is life-changing and could be said after-effects last for a lifetime.
 
There is no single "longest lasting" drug as the duration of a drug's effect depends on various factors, including its pharmacokinetics, metabolism, and individual patient factors. However, some drugs may have a longer duration of action than others, which can make them useful in certain clinical settings.

For example, buprenorphine, a medication used to treat opioid addiction, has a longer duration of action compared to other opioids due to its high affinity for the mu opioid receptor and slow dissociation from the receptor. This allows for once-daily dosing in some patients.

Similarly, certain long-acting insulin formulations, such as insulin glargine and insulin degludec, have a longer duration of action than regular or rapid-acting insulin due to their slow release from subcutaneous tissue into the bloodstream. This allows for once-daily or even once-weekly dosing in some patients with diabetes.

However, it is important to note that the effectiveness and safety of a drug depend on multiple factors, and a longer duration of action does not necessarily mean that a drug is better or more effective. Healthcare professionals should always consider individual patient factors and carefully weigh the risks and benefits of a drug before prescribing it.
 
I think enzyme inhibitors are going to be some of the longest lasting drugs. There have been made opioids which alkylate the mu receptor, but the constant activation gets the receptors internalized pretty quickly.
 
AlsoTapered said:
Bromo-Dragonfly is a compound that REALLY needs a sacrificial moiety. Some simple metabolic pathway to allow the body to remove it. That said, isn't the 2-carbon version still pretty potent and has a more reasonable duration. I mean, does bromo dragonfly do something SO unique that it make that duration worthwhile?

The team at Perdue found that the benzylpiperidines also had 5HT2a affinity so I wonder if it's possible to make 2,5-dimethoxy-4-bromo Ritalin (for example) or 2,5-dimethoxy-4-brtomo DEXTROphacetorperane because levophacetorperane is the wrong optical isomer for 5HT2a affinity. Both of those have esters so short durations.
Click to expand...
Here is the new, shorter acting, bromo-dragon-methylphenidate.

bromo-dragon-methylphenidate.jpg
 
AlsoTapered said:
Ever noted how many different medical conditions it was trialled for the treatment of?

Be REALLY careful because usually behind such a compound is a company in dire need of a cash-cow. If they put ALL of their chips on 1 compound, bad luck.

I've worked in drug discovery and 7 out of 10 candidates fail during animal studies, the rest... well 9 out of 10 of those will fail in human trials.

Small start-up are risky and knowing the venture capital people, they expect 9 out of 10 to fail! And that's with experts who REALLY look into the development and important related details such as patents.

If it's natural, you can only patent the usage. Even then you either make the patent narrow but strong, or broader but weaker....

The recent patent on tryptamines is weak. I could find an example with a specific use and STILL be able to get another patent. OK I may have to pay the people with the broad patent some... but that was the point of the tryptamine patent. To cash in on ANY drug their massive library covered.

Me, I've patented 3 compounds at MOST but if they are used, I can firmly state that I got there first.
Click to expand...
THE GREAT STORY OF TAXOL
NON PAY WALL
 
Last edited:
IbenHatab said:
There is no single "longest lasting" drug as the duration of a drug's effect depends on various factors, including its pharmacokinetics, metabolism, and individual patient factors. However, some drugs may have a longer duration of action than others, which can make them useful in certain clinical settings.
Click to expand...

Ofc but yet here I am and a lot of people I know who all tried a lot of various drugs but we all had longest lasting high on DOC or DOI. I’m wondering about even longer lasting drugs.
 
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