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Pharmacology Are ultra long-acting drugs possible?

This thread contains discussion about a Pharmacology-related topic
red22

red22

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Quotes from The Shroomery:

Sugabearcrisp said:
Deuterated drugs are interesting, great to see treatments for plaque psoriasis, huntington's and cystic fibrosis being created. AVP-786 is deuterated dxm and has been trialed for dimentia related agitation. S240779 As you describe in your post deuteration of the drug slows enzyme metabolism, increasing half life of the drug and reduction in toxic metabolites.



So cybin's two deuterated molecules derive from psilocin (4-ho-dmt) and dmt. Deuterating these likely has the same effect of reducing metabolic rate and increasing half life, i.e. a long half life microdose.

It makes me wonder... why not use a longer half life pyschedelic like lsd, mescaline, the DOx compounds, or bromo dragonfly? I'm imagining the dose response curve would make this difficult, oops we gave grampa too much deuterated DOM, he's tripping for 2 weeks straight, lol


s240779 said:
Deuterating these likely has the same effect of reducing metabolic rate and increasing half life, i.e. a long half life microdose.​

On top of that, you can formulate it for a depot injection.


Sugabearcrisp said:
I shudder to imagine what a depot injection formulated deutarated bromodragonfly would have for a duration.



 
You'd most likely have to add an Ester such as Decanoate or Enanthate to the Molecules Molecular structure to make it longer acting.
 
Imagine making a depot injection of Penfluridol. That would be an injection of an Antipsychotic that lasts up to 6 to 8 months.
 
bromides?

agreed, otherwise definitely possible, if not the drugs themselves then in how depot shots are formulated--six-month-long invega shots at this point. i imagine they'll have 12-month shots in not too long.

tons and tons of drugs that haven't been discovered, we're just scratching the surface still
 
AlphaMethylPhenyl said:
tons and tons of drugs that haven't been discovered, we're just scratching the surface still
Click to expand...

𝚀𝚞𝚘𝚝𝚎:

Olefins are useful in pharmaceutical research, but Bredt’s rule has constrained the kind of synthetic molecules scientists can imagine making with them and prevented possible applications of their use in drug discovery.

A new paper published by UCLA scientists in the journal Science has invalidated that idea. They show how to make several kinds of molecules that violate Bredt’s rule, called anti-Bredt olefins, or ABOs, allowing chemists to find practical ways to make and use them in reactions.

[ … ]

“There’s a big push in the pharmaceutical industry to develop chemical reactions that give three-dimensional structures like ours because they can be used to discover new medicines,”

 
How about some of the irreversible ligands? That's gotta be the longest lasting it could get. Only thing standing in its way is biology cos the receptor just eats itself eventually.
 
JitteryKitteryDoo said:
How about some of the irreversible ligands? That's gotta be the longest lasting it could get. Only thing standing in its way is biology cos the receptor just eats itself eventually.
Click to expand...
Yes things like Oxymorphazone, unfortunately the receptor seems to permanently downregulate/eat itself like you said.

I remember people theorizing that some astatine subbed phenethylamines might cause irreversible binding as well but I doubt it. An irreversibly binding 2C-x or 25xNBxx sounds fucking bonkers though
 
TheLightBringer said:
Yes things like Oxymorphazone, unfortunately the receptor seems to permanently downregulate/eat itself like you said.

I remember people theorizing that some astatine subbed phenethylamines might cause irreversible binding as well but I doubt it. An irreversibly binding 2C-x or 25xNBxx sounds fucking bonkers though
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Definitely not for the weak willed. My mind would crack into a million pieces if I did anything like that. Even a standard dose of 25i-NBOMe sent me off the rails. I recoil in embarrassment thinking how wrong that night went. Never again. Thank all my lucky stars that it was only temporary.

What was the deal with that drug that destroys the dopamine receptors again?

Oh man, I had to look it up... That MPTP compound that causes irreversible parkinsons. I haven't done a deep dive on that yet, but it is so fascinating to think that it's even possible.
 
JitteryKitteryDoo said:
Definitely not for the weak willed. My mind would crack into a million pieces if I did anything like that. Even a standard dose of 25i-NBOMe sent me off the rails. I recoil in embarrassment thinking how wrong that night went. Never again. Thank all my lucky stars that it was only temporary.

What was the deal with that drug that destroys the dopamine receptors again?

Oh man, I had to look it up... That MPTP compound that causes irreversible parkinsons. I haven't done a deep dive on that yet, but it is so fascinating to think that it's even possible.
Click to expand...
Haloperidol
 
I think you are alluding to mppp. MPTP is an interesting agent and many drugs have been made from it either directly or analogs thereof.

Kalgutkar AS, Castagnoli N Jr. Synthesis of novel MPTP analogs as potential monoamine oxidase B (MAO-B) inhibitors. J Med Chem. 1992 Oct 30;35(22):4165-74. doi: 10.1021/jm00100a023. PMID: 1433219.

Phenindamine [82-88-2]
ALX-0646 [208464-67-9]
EMD-23448 [73966-53-7]
Trabuton & Anisoperidone & Roxindole & Fenpipalone

To synthesize femoxetine.

Engelbert Ciganek, US4485109 (1984 to Bristol Myers Squibb Pharma Co).

Jr Frank H Clarke, US3320265 (1967 to Novartis Corp).
Fred B Block & Jr Frank H Clarke, US3341538 (1967 to Novartis Corp).
Dexter Martin, US3417094 (1968 to Novartis Corp).
Yokoyama N, Almaula PI, Block FB, Granat FR, Gottfried N, Hill RT, McMahon EH, Munch WF, Rachlin H, Saelens JK, Siegel MG, Tomaselli HC, Clarke FH. Syntheses, analgetic activity, and physical dependence capacity of 5-phenyl-6,7-benzomorphan derivatives. J Med Chem. 1979 May;22(5):537-53. doi: 10.1021/jm00191a016. PMID: 37335.
 
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Smyth2 said:
I think you are alluding to mppp. MPTP is an interesting agent and many drugs have been made from it either directly or analogs thereof.

Kalgutkar AS, Castagnoli N Jr. Synthesis of novel MPTP analogs as potential monoamine oxidase B (MAO-B) inhibitors. J Med Chem. 1992 Oct 30;35(22):4165-74. doi: 10.1021/jm00100a023. PMID: 1433219.
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From what I was reading I was under the impression that the toxic compound is the metabolite of MPTP, which looks to be a side product of MPPP. So if someone consumes the precursor to the neurotoxin, MAOIs can be used to prevent the MPTP from getting converted to MPP+

It's all very fascinating. I'm always wanting to learn and understand more.
 
TheLightBringer said:
Interestingly enough Haloperidol and other antipsychotics upregulate and can increase the amount of dopamine receptors.

Sometimes leads to dopamine supersensitivity
Click to expand...
This is correct, but good luck getting a doctor to admit that. Or anyone else in healthcare work. Pretend that withdrawal only happens with habit forming medications.

There's also AP induced cholinergic rebound associated with certain antipsychotics like clozapine
 
TheLightBringer said:
I remember people theorizing that some astatine subbed phenethylamines might cause irreversible binding as well but I doubt it. An irreversibly binding 2C-x or 25xNBxx sounds fucking bonkers though
Click to expand...
I feel like an astatine substitution would be like giving radioactive iodine isotopes to ablate the thyroid. You would get selective destruction of serotonin 2A containing cells.

The real move would be to stick something like a hydrazine, isocyanate, bis-chloroethylamine, or cinnamyl group somewhere that doesn’t destroy activity if you want an irreversible binder.

That being said, irreversible binders seem to really pump the gas on receptor internalization. Homeostatic mechanisms have evolved to be quite robust.
 
I found some extremely long duration drugs while I was combing the literature.

Solmssen, Ulrich V. (1945). "Synthetic Estrogens and the Relation Between their Structure and their Activity.". Chemical Reviews. 37 (3): 481–598. doi:10.1021/cr60118a004.

Forward to triphenylethylene derivatives (page 542) and read for yourself.

ROBSON, J., SCHÖNBERG, A. A New Synthetic Œstrogen with Prolonged Action when Given Orally. Nature 150, 22–23 (1942). https://doi.org/10.1038/150022a0

ROBSON, J., SCHöNBERG, A. & FAHIM, H. Duration of Action of Natural and Synthetic Œstrogens. Nature 142, 292–293 (1938). https://doi.org/10.1038/142292a0
 
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