⫸STICKY⫷ Drawing random molecules v.2 doodling in class instead of taking notes

[AlsoTapered]

It’s good to see you being productive even though you are disabled and to see you doing things by the book. My situation is not as bad as yours but I still can’t approach it with your level of virtue for lack of a better word.

I’m able bodied but live with chronic pain and 99% of my use is of legal narcotics as prescribed for about 5 years now. I would still class myself as a drug addict due to last history and cravings to let go and return to abusing Narcs.

I struggle daily with suicidal thoughts and cravings to return to the illicit drugs due to the prison ones body can be.

Do you struggle with thoughts of self destructive or hard drug abuse due to your condition?

Except for weed I abuse the hell out of weed.

Drugs are a temporary solution to a long-lived problem.
Suicide is a permanent solution to temporary problem.

I've watched someone die as their kidneys failed. So I stay alive because should a severe head injury occur, At least I can give others the chance. Heart, lungs, kidneys, eyes and so forth. Suicide means an inquest so those organs help nobody.

BTW Why are you moving the amine away from the aryl moiety? Note dizocilpine, the prototype NMDA antagonist or diphenidine. Their has to be an aryl just 1 methylene from the aryl. Identify the key moieties and consider their spatial relationship (including the N.

The first effort was so close - just the LogP which, BTW, you could have brought down by adding a ketone. Where? Dunno.

1-(3-Methyl-4-thiophen-2-ylthian-4-yl)piperidine

1-(3-Methyl-4-thiophen-2-ylthian-4-yl)piperidine | C15H23NS2 | CID 15408084 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.

pubchem.ncbi.nlm.nih.gov

Follow the patents - voila, 78 NMDA antgonists/DRIs.

 

[LucidSDreamr]

Drugs are a temporary solution to a long-lived problem.
Suicide is a permanent solution to temporary problem.

I've watched someone die as their kidneys failed. So I stay alive because should a severe head injury occur, At least I can give others the chance. Heart, lungs, kidneys, eyes and so forth. Suicide means an inquest so those organs help nobody.

BTW Why are you moving the amine away from the aryl moiety? Note dizocilpine, the prototype NMDA antagonist or diphenidine. Their has to be an aryl just 1 methylene from the aryl. Identify the key moieties and consider their spatial relationship (including the N.

The first effort was so close - just the LogP which, BTW, you could have brought down by adding a ketone. Where? Dunno.

1-(3-Methyl-4-thiophen-2-ylthian-4-yl)piperidine

1-(3-Methyl-4-thiophen-2-ylthian-4-yl)piperidine | C15H23NS2 | CID 15408084 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.

pubchem.ncbi.nlm.nih.gov

Follow the patents - voila, 78 NMDA antgonists/DRIs.

Were you ever a bona fide drug addict or some kind of recreational user? Is this the main area of pharmacology you are interested in? Or is it just one of many different areas that you research with your time? Is it just pharmacology related to recreational drugs/narcotics you like or all of neuropsychopharmacology?


I’m wondering because it seems like most people that end up interested in this niche have a drug” “abuse” history. I understand some people take a subset of these drugs (ie opioids) for non recreational purposes and maybe that’s you so that’s why you were drawn here.

Re the solution to problems quotes you mentioned….that outlook does speak to the fact that you’re not an addict. All an addict cares about is solving the current problem by whatever means needed (drugs or suicide) without considering the future at all.

I don’t agree that suicide is a solution to a temporary problem in all cases. If it really is something permanent the person is trying to escape…well it’s only temporarily in the sense that it ends when they die naturally, so what’s the difference of dying sooner besides the organ donation issue you mentioned ?

 

[AlsoTapered]

It was my field in further education.

I don't have anything else I can so,

And HOPE, everyone's 'choices' are half chance so whatever today threw at you, tomorrow might be better.

The vast MAJORITY of the world's population would laugh at how petty our problems are. Many don't even posses the very bottom rung of Maslow's hierarchy of needs:

Air
Water
Food
Heat
Clothes
Urination
Excretion
Shelter
Sleep

Security and safety are what they dream of. So in truth, we still 'won the birth lottery'.

And drugs? I couldn't afford weed. I can barely afford to eat. But tomorrow might be better,

 

[LucidSDreamr]

It was my field in further education.

I don't have anything else I can so,

And HOPE, everyone's 'choices' are half chance so whatever today threw at you, tomorrow might be better.

The vast MAJORITY of the world's population would laugh at how petty our problems are. Many don't even posses the very bottom rung of Maslow's hierarchy of needs:

Air
Water
Food
Heat
Clothes
Urination
Excretion
Shelter
Sleep

Security and safety are what they dream of. So in truth, we still 'won the birth lottery'.

And drugs? I couldn't afford weed. I can barely afford to eat. But tomorrow might be better,

But what I’m asking is if you chose that specific niche in higher education due to prior recreational drug use or that’s just the lab you got the best possible spot in or something like that, while having had no interest or prior experience with drugs recreationally or addiction wise

As far as my only problem goes,
I wouldn’t say physical pain is any easier to feel whether you’re as rich as Bezos or feeling it on the floor of a hut in rural Afghanistan with 30 cents to your name….then again if you’re in rural Afghanistan there are endless fields of opium growing on the ground so maybe it’s a little easier there.

Anyways,
I admire your positive attitude in the face of heavyproblems, in fact I’m somewhat jealous of it.

 

[AlsoTapered]

No - as a teen a close friend developed schizophrenia. He had used a lot of drugs. But in truth, I don't think drugs were the problem, they were self-medication. A huge series of bad things all happened to him in just 1 week: So I wanted to understand
the disease and to improve outcomes.

But some life stuff got in the way.

So Id this - the closest I can get to using my skillset.

 

[pharmakos]

BTW Why are you moving the amine away from the aryl moiety? Note dizocilpine, the prototype NMDA antagonist or diphenidine. Their has to be an aryl just 1 methylene from the aryl. Identify the key moieties and consider their spatial relationship (including the N.

The first effort was so close - just the LogP which, BTW, you could have brought down by adding a ketone. Where? Dunno.

Pure curiosity, I knew it would get rid of the NMDA activity.

I messed around with diphenidine analogues for awhile after that post. And methylphenidate analogues. Found a few interesting molecules, turns out methylphenidate analogues with a cyclohexyl in place of the acetate can have 5HT-2a activity. Might upload the images later.

Adding a ketone was my first idea, tried a couple positions, didn't work out. Didn't try every position, tho. Can't stick it in the "classic" position without resulting in a Texas carbon or course.

 

[AlsoTapered]

If you followed the patents, the MOST potent is 1-[(3S,4S)-3-methyl-4-(thiophen-2-yl)thian-4-yl]piperidine which has sub-nM affinity.

Don't confuse affinity and activity. a drug can be anywhere from a superagonist to an antagonist, That said, Ralf Helm has already explored the phenylpiperidine class and produced some very potent 5HT2a agonists,

A good lesson is to read what has already been done. If you draw something and copy it's SMILES definition into PubChem, if it's known, it spits out the papers and patents.

Almost everything that SEEMS obvious will also seem obvious to a researcher...who has a lab.

Yes in-silico design is possible, but you need ChemOffice and access to Reaxys at least.

The former I was gifted, the latter... I know people at Imperial Collage (who have unlimited Reaxys searches)

TBH read all of the papers and patents you can find. We added a thread that is called 'Useful neuroscience/pharmacology threads'
and it has books, papers and articles. Hundreds of them. And those were chosen carefully. No fat. It's ALL useful.

No point in re-inventing the wheel. LOOK at how researchers work by finding the original patent of a drug:

I use a Japanese language site but their is a cheat: I google 'drugfuture.com chlorodiazepoxie' (if I want the chlorodiazepoxide papers and patents and returns them in English thus:

Chlordiazepoxide

Then you use Google Patents, it will tell you all later patents that reference the one you are reading so you can quickly see how a class was developed,

PubChem sometimes doesn't have as much but it might be easier for you.

PubChem

PubChem is the world's largest collection of freely accessible chemical information. Search chemicals by name, molecular formula, structure, and other identifiers. Find chemical and physical properties, biological activities, safety and toxicity information, patents, literature citations and more.

pubchem.ncbi.nlm.nih.gov

But either way - look at each of the classes of commonly abused drugs. You will soon see how it all works.

 

[pharmakos]

If you followed the patents, the MOST potent is 1-[(3S,4S)-3-methyl-4-(thiophen-2-yl)thian-4-yl]piperidine which has sub-nM affinity.

Don't confuse affinity and activity. a drug can be anywhere from a superagonist to an antagonist, That said, Ralf Helm has already explored the phenylpiperidine class and produced some very potent 5HT2a agonists,

A good lesson is to read what has already been done. If you draw something and copy it's SMILES definition into PubChem, if it's known, it spits out the papers and patents.

Almost everything that SEEMS obvious will also seem obvious to a researcher...who has a lab.

Yes in-silico design is possible, but you need ChemOffice and access to Reaxys at least.

The former I was gifted, the latter... I know people at Imperial Collage (who have unlimited Reaxys searches)

TBH read all of the papers and patents you can find. We added a thread that is called 'Useful neuroscience/pharmacology threads'
and it has books, papers and articles. Hundreds of them. And those were chosen carefully. No fat. It's ALL useful.

No point in re-inventing the wheel. LOOK at how researchers work by finding the original patent of a drug:

I use a Japanese language site but their is a cheat: I google 'drugfuture.com chlorodiazepoxie' (if I want the chlorodiazepoxide papers and patents and returns them in English thus:

Chlordiazepoxide

Then you use Google Patents, it will tell you all later patents that reference the one you are reading so you can quickly see how a class was developed,

PubChem sometimes doesn't have as much but it might be easier for you.

PubChem

PubChem is the world's largest collection of freely accessible chemical information. Search chemicals by name, molecular formula, structure, and other identifiers. Find chemical and physical properties, biological activities, safety and toxicity information, patents, literature citations and more.

pubchem.ncbi.nlm.nih.gov

But either way - look at each of the classes of commonly abused drugs. You will soon see how it all works.

I mean delete this thread then, what's it even for in that case? Lol

 

[pharmakos]

A good lesson is to read what has already been done. If you draw something and copy it's SMILES definition into PubChem, if it's known, it spits out the papers and patents.

Btw, I did try that with many of the compounds I drew, and found nothing.

And also, nitpicky note, but the psychedelics I posted were not piperidines.

 

[pharmakos]

Is this a known class of compounds? Did one of my usual amateur ideas I tend to do when I'm playing around with SAR, noticed that moving that nitrogen "over" one gives a phenethylamine skeleton. First attempt showed decent transporter binding. Played around with all the obvious substitutions til I landed on this.



CNC(C)C1(CCCCC1)C1=CC=CC(F)=C1
1-[1-(3-fluorophenyl)cyclohexyl]-N-methylethanamine
LogP 3.8

The 4-trifluoromethyl has slightly better binding predicted, but a less favorable LogP, 4.47.

Lots of the other obvious substitutions one would think of for phenethylamines also work (i.e. alkyl instead of fluoro, longer alkyl groups on the "alpha" carbon or the nitrogen, removing those carbon atoms, etc). These two^ were the ones with the most favorable predictions for transporter binding tho.

4-methyl is the only substitution that adds 5-HT2a activity.



CC1=CC=C(C=C1)C1(CN)CCCCC1
[1-(4-methylphenyl)cyclohexyl]methanamine
LogP 3.81

I should have systematically saved the SMILES formulas for the rest of that post, rather than needing to rebuild the structure if I want to revisit them. These two, however, go ahead and Google search and you will find next to nothing. A few generic pages with the structure, pages so generic that I'm quite sure they were generated by systematic algorithmic automation, rather than by a human hand directly. No research or anything past that.

Chemistry is a big world, not everything has been tried by any means, not even close. There's a reason that AI is being used to quickly churn through ideas, because the iceberg is that big, and we've only just seen the tip of it. With AI we may someday reach a point where the "throwing shit at the wall and hoping it sticks" method like this is pointless. But we are surely not there yet.

 

[AlsoTapered]

Btw, I did try that with many of the compounds I drew, and found nothing.

And also, nitpicky note, but the psychedelics I posted were not piperidines.

I clearly wasn't replying to you.

 

[pharmakos]

I clearly wasn't replying to you.

Huh? Genuinely wasn't clear if so. Your post functioned when considered as a response to my post directly before it... just looked like you quoted the wrong post. The post you quoted originally replying to wasn't even talking about SAR...

 

[polymath]

(1-Trichloromethyl)ethanol, a derivative of chloral and chlorbutanol, has two stereoisomers and it would be interesting to see if there's a difference in their CNS depressant effects. I think this compound was used as a sedative some 100 years ago or so, but I can't remember what name it was called.

Ethyl 2-butyl ether also has an R and S isomer. Ethyl propenyl ether can exist in cis and trans forms, but there's a risk that it is toxic in some way even though divinyl ether was also used as an anesthetic in the past and the C-C double bonds didn't cause any extra toxicity in that case. A benefit of the double bond there is that it's probably destroyed metabolically much faster than Et₂O, so it doesn't make you stink of volatile solvent for the next 24 hours.

Some chiral volatile anesthetics have actually been observed to have a difference in potency between R and S forms, but the subjective psychoactive effects haven't been tested in humans.

 

[AlsoTapered]

(1-Trichloromethyl)ethanol?

I knew that some inhalational anesthetics were chiral but it's interesting that they demonstrate differing MAC numbers. Desflurane, enflurane and methoxyflurane are also chiral. Since the fluorinated ethers display hepatotoxicity, it MAY be a methodology of reducing said toxicity, but I imagine a chiral synthesis would be costly and the difference in MAC numbers isn't vast - or at least not in the examples I know of.

 

[polymath]

(1-Trichloromethyl)ethanol?

Yeah, a typo, should have read 1-(trichloromethyl)ethanol or 1,1,1-trichloro-2-hydroxypropane.

I believe the chloral like compounds and also paraldehyde act by a mechanism similar to ethanol, 2m2b and volatile anesthetics.

 

[AlsoTapered]

Clenbuterol. Yes, it was used to dope greyhounds. Apparently their was a famous case in the UK in which every dog was doped with the material apart from a 25/1 outsider. Apparently the bookmakers lost £100,000 which in 1952, was a LOT of money. It was referred to as the 'White City Scandal' but given the limited ability to test for doping, even the police were unable to press charges.

Eddie Chapman (Agent Zigzag) was famously behind it. He got about 60 people to spread bets across the 60 odd bookies. Normally bookmakers will offset their risk among other bookmakers but that night, their was no way to 'lay off' their risk and it bankrupted about 12 of them.

So I think it's reasonable to suggest that it is indeed a CNS depressant... or, at least, it reliably makes greyhounds run significantly more slowly.

 

[polymath]

Chlorobutanol - Wikipedia

en.wikipedia.org

This was created to be an alternative for chloral hydrate, but it has a half-life of several days due to the difficulty of oxidizing a tertiary alcohol and therefore accumulates in your system. Much like trying to use phenobarbital as a hypnotic.

 

[AlsoTapered]

Does it accumulate? I thought it was simply excreted unchanged. While unusual, it's not alone in that. Even things like pregabalin are excreted by the kidneys 97% unchanged.

 

[polymath]

Some article I now can't immediately find had a case report of someone having been in stupor state for more than two weeks after using chlorobutanol excessively and accumulating it in his system. They measured the half life of the drug to be more than a week long, but it's possible that it's less when it's not an overdose situation.

 

[AlsoTapered]

I would certainly be interested to read. As with all drug excretion, their is a limiting step. If intake is huge, it could well take a long time for it to be excreted.

I wonder if that rate is faster in dogs? One would imagine that if dozens of them were doped and the effects lasted for weeks, it would be quite evident. Sadly, although the news media of the time reported on the 'White City Scandal', in 1952 I doubt any testing would be possible - especially since the precise nature of the material was unknown.

If memory serves, the bis-sulfonyl class of hypnotic (Sulfonal, Trional, Tetranol) had a very slow onset and very long duration of action. The latter were more lipophilic (so faster acting) and I suspect had a shorter duration of action since those alkyl chains can be more readily oxidized.