I Like to Draw Pictures of Random Molecules

[Nagelfar]

This started as a phenyltropane, would you believe it? I sketched it at home freehand, turned what the aryl became into a replacement for the tropane base, and with what remained attempted to make it overlap (in 2D mind you, probably not in 3D) with a phenyltropane (in a back-formation of the original)

Comments would amuse me. Humor me.

 

[aced126]

This started as a phenyltropane, would you believe it? I sketched it at home freehand, turned what the aryl became into a replacement for the tropane base, and with what remained attempted to make it overlap (in 2D mind you, probably not in 3D) with a phenyltropane (in a back-formation of the original)

Comments would amuse me. Humor me.

So many comments to make...so many

I will resist the urge.

 

[DotChem]

Interesting molecule.

 

[DotChem]

Methylphenadil

would make you very smart

 

[DotChem]

early never-marketed/discontinued anti-depressants with interesting skeletons:

Tranylcypromine

Carbenzide

Isocarboxazid

Iproniazid

Metfendrazine

Domoxin

Cimemoxin

Humans are animals, taxonomic genus "Homo", I am as right/correct as the Elephant Man; but I'm not his clone (I hope, my mirror is the same as Shallow Hal's if not)

Hydrazides ( molecules containing -NH-NH-CO- group) were withdrawn from market because pretty much all the hydrazides and the hydrazines give you liver cirrhosis at low doses. like a drinker of a pint of scotch every day for 50 years!

 

[Nagelfar]

Hydrazides ( molecules containing -NH-NH-CO- group) were withdrawn from market because pretty much all the hydrazides and the hydrazines give you liver cirrhosis at low doses. like a drinker of a pint of scotch every day for 50 years!

How long with the indicating dosing did the hydrazides = the affect on the liver of a pint of scotch daily for a half-century? or is this a rhetorical summation of a comparison?

Methylphenadil

would make you very smart

The ethyl is a "v.(ery)" and the sulfur means "smart". I think I've discovered a hidden truism, rhyme and reason, behind chemistry.

So many comments to make...so many

I will resist the urge.

That counts. Taken. (now, if someone can shoot some holes in it, I'll be indebted. I learn through my immense capacity for folly and blunders of large magnitude and the attention they draw. I read in Utah it is illegal to "cause a catastrophe", within the midst of the abstract professional field of academics: I'm glad I live in WA state.

 

[roi]

 

[Solipsis]

hehe

jimmy! stop making sufent propethidine analogues!

I wasnt mom! its just an mpa analogue!

[would generate less nor metabolite?]

 

[roi]

Should be at least 50x fentanyl.

 

[DotChem]

Word of Caution: Reverse esters of pethidine (OCOEt instead of -COOEt) easily (ie normal physiological conditions) give rise to neurotoxic MPTP and MPP+ via elimination(of OCOEt)/oxidation of the methylpipiperidine... The RC chemists back in the 80s who tried it found out the hard way: they ended up "frozen" with permanent irreversible Parkinson!

MPPP

The neurotoxicity of MPTP was hinted at in 1976 after Barry Kidston, a 23-year-old chemistry graduate student in Maryland, US, synthesized MPPP with MPTP as a major impurity, and self-injected the result. Within three days he began exhibiting symptoms of Parkinson's disease. The National Institute of Mental Health found traces of MPTP and other pethidine analogs in his lab. They tested the substances on rats, but due to rodents' tolerance for this type of neurotoxin nothing was observed. Kidston's Parkinsonism was treated with levodopa but he died 18 months later from a cocaine overdose. Upon autopsy, destruction of dopaminergic neurons in the substantia nigra was discovered.^[6]

In 1982, six people in Santa Clara County, California, US, were diagnosed with Parkinsonism after having used MPPP contaminated with MPTP. The neurologist J. William Langston in collaboration with NIH tracked down MPTP as the cause, and its effects on primates were researched. The motor symptoms of two of the seven patients were eventually successfully treated at Lund University Hospital in Sweden with neural grafts of fetal tissue.^[7]
Langston documented the case in his 1995 book The Case of the Frozen Addicts, which was later featured in two NOVA productions by PBS, re-aired on the UK on the BBC programme Horizon.^[8]

https://en.wikipedia.org/wiki/MPTP


more from wiki entry:

Injection of MPTP causes rapid onset of Parkinsonism, hence users of MPPP contaminated with MPTP will develop these symptoms.
MPTP itself is not toxic, and as a lipophilic compound can cross the blood–brain barrier. Once inside the brain, MPTP is metabolized into the toxic cation 1-methyl-4-phenylpyridinium (MPP+) by the enzyme MAO-B of glial cells. MPP+ kills primarily dopamine-producing neurons in a part of the brain called the pars compacta of the substantia nigra. MPP+ interferes with complex I of the electron transport chain, a component of mitochondrial metabolism, which leads to cell death and causes the buildup of free radicals, toxic molecules that contribute further to cell destruction.....etc

https://en.wikipedia.org/wiki/MPTP

 

[DotChem]

How long with the indicating dosing did the hydrazides = the affect on the liver of a pint of scotch daily for a half-century? or is this a rhetorical summation of a comparison?

Enough to inhibit their target MAO because they're irreversible MAO inhibitor. If I recall even a single dose make small holes in the liver which of course the Pharma companies developing the drugs didn't tell anybody till they recoup the $$ they've invested (including class action laywers cut$$ too!

The ethyl is a "v.(ery)" and the sulfur means "smart". I think I've discovered a hidden truism, rhyme and reason, behind chemistry.

Not that the sulfur make smart .. but it looks (and i think will behave) like nootropic Modafinil (with the sulfoxide somehow off tho ..) AND methylphenidate (with methyl ester of MPH bioisosteric replacement by SOEt).... easy to synthesize (just need testers ala Shulgin!!

 

[Solipsis]

So piracetam hydrazide is very dangerous? Seems worth putting a warning in the nootropics thread?

 

[roi]

Both piracetam hydrazide and phenylpiracetam hydrazide have been sold for quite a while and there aren't any "harmful" reports on it afaik.

 

[DotChem]

Carbohydrazides like isoniazid are known to be hepatotoxic since 80s. here is a ref and a proposed model of how they wreck havoc in the liver where they get metabolized by oxidases. you can find lots of other refs.

"Direct Oxidation and Covalent Binding of Isoniazid to Rodent Liver and Human Hepatic Microsomes: Humans Are More Like Mice than Rats"
Uetrecht et al (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501148/)

soniazid (INH) is associated with serious liver injury and autoimmunity. Classic studies in rats indicated that a reactive metabolite of acetylhydrazine is responsible for the covalent binding and toxicity of INH. Studies in rabbits suggested that hydrazine might be the toxic species. However, these models involved acute toxicity with high doses of INH, and INH-induced liver injury in humans has very different features than such animal models. In this study, we demonstrated that a reactive metabolite of INH itself can covalently bind in the liver of mice and also to human liver microsomes. Covalent binding also occurred in rats, but it was much less than that in mice. We were able to trap the reactive metabolite of INH with N-α-acetyl-l-lysine in incubations with human liver microsomes....blablabla

Later hydrazides (me-too drugs related to isoniazid, like the one cited by @nafelgar) were also found to be as bad or worse in humans and mice (but NOT RATS!!). Rats metabolize them differently.


Even though one cannot generalize to EVERY SINGLE HYDRAZIDE containing drug, chances are they can be expected to get metabolized similarly to isoniazid at least the one containing the Aryl-CO-NH-NH2 type..(good substrate for liver oxidase)


As for phenylpiracetam hydrazide I wouldn't be surprised if it too gives the same type of hepatotoxcity. As far as one can tell, no formal study of users of this drug has been done (corretc me if I am wrong). So one cannot exlude liver problem. This kind of problem may not be as obvious as say problem with opiates (YOU DROP DEAD if something do wrong!) so it is hard to tell your liver is getting chewed by the drug. Advanced clinical investigations such as liver biopsy to detect it will be needed or like alcohol cirrhosis only when it is too advanced that anything pain will be felt (by then its too late..you may need a new liver!). + if you're heavy drinker it will make it worse and complicated the picture further.


So I think until more is known on phenylpiracetam hydrazide and Liver issues, one must avoid at the very least chronic use of this molecule just to be cautious. But it may be metabolized differently from isoniazid ..who knows?


PS: that article title? (I personally believe humans are more like rats. I know lots of them! rats..

 

[Bagseed]

This started as a phenyltropane, would you believe it? I sketched it at home freehand, turned what the aryl became into a replacement for the tropane base, and with what remained attempted to make it overlap (in 2D mind you, probably not in 3D) with a phenyltropane (in a back-formation of the original)

Comments would amuse me. Humor me.

lol

 

[Dresden]

3-Chloro

 

[Dresden]

3-Methyl-MXE

 

[Dresden]

A (potentially genius) hybrid of methamphetamine and Strattera.

 

[adder]

When a drug binds very strongly, it doesn't continue to keep increasing net activation just like hugging someone is not always the more pleasant the longer they continue to hang on.

I understand that affinity is just a measure of at what concentration 50% of radioligand molecules are displaced by a ligand of interest from the receptor, so this has nothing to do with dissociation time from the receptor, right? I suppose both etorphine and buprenorphine fit well into your hugging analogy even though one is a full mu agonist and the other only a partial agonist, but they both have long dissociation times.

 

[Solipsis]

Yeah I think it will depend on whether it keeps a receptor in activated conformation while occupying?

I wasn't really trying to in a general sense define any singular pharmacology term but mentioned mixed agonists / agonist-antagonists, and was musing on those peculiar drugs that are very potent agonists but have slightly modified analogues that are potent antagonists. Not that I have an actual proof that the novel benzo I tried is an agonist-antagonist but it's certainly interesting how it is a very close analogue to known potent benzo agonists, and exhibited agonist-antagonist effects. Pretty consistently, but it remains my subjective experience.

Also I wouldn't think that affinity has nothing to do with dissociation time, because if there is more optimal binding energy (difference between intermediate state with bound/unbound state) doesn't that lead to longer dissociation time since that energy is not so easily overcome? It seems like that would mean that it would at least be one of the factors if not the only one in net displacement since even if one or the other ligand does bind 'better' than the other one, when the long-occupying one IS actually bound to it, during that time there is no competition possible.
I don't know that it's possible for the better binding one not to be the long occupying one by definition.
And I don't really know the time scales for binding of high affinity drugs, the period of time bound compared to the receptor being free (though I randomly heard numbers like 60 or 80% of receptor occupancy being possible with some drugs, not even being a limit?)... but unless dissociation time is actually insignificant in this perspective, it seems like it would come into picture?

edit:
Hopefully I am not taking anything out of context, but if the well versed mr serotonin2a says:

Opioids that bind with high affinity (slow dissociation)

http://www.bluelight.org/vb/threads...-Acid-in-solution-with-Acetylfentanyl-Acetate

it seems my thinking is on the right track?