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N&PD Moderators: Skorpio | someguyontheinternet
The Big and Bangin' Pseudo-Advanced Drug Chemistry, Pharmacology and More Thread, V.2
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Epsilon Alpha
Bluelighter
Well L-DOPA is the precursor for NE as well, it kind of goes like this:
L-DOPA---(DOPA decarboxylase)----->Dopamine-----(Dopamine Beta hydroxylase)----->NE
I really can't say what would happen as far as total effects go though, stuff gets complicated fast with the whole autoreceptor, tonic/phasic levels, and where the COMT has its greatest effects. Off the top of my head I recall some COMT inhibitors having nasty side effects due to peripheral issues or some sort of other effect, but I recall orange urine was a side effect for one of them.
Also, we really are lacking in studies that display their effects in healthy individuals, or even ADHD for that matter.
Wouldn't COMT inhibitors have to cross the BBB to increase DA/NE levels directly? Tolcapone does this and is hepatoxic. Entacapone will not cross BBB and isn't hepatoxic but will just increase L-DOPA, which is going to give those nasty side effects (and I guess L-DOPA would cross the BBB, which it sucks at, and increase CNS DA/NE). Theoretically, tolcapone would work for ADHD, as it would target COMT which is most abundant in the prefrontal cortex. It's interesting though, that most MAO-A/B inhibitors have been shown to not improve ADHD, and some of them do not even amplify DA/NE transporter inhibitors, cocaine was found to not be affected, for example. "Moreover, these findings suggest that adverse consequences related to altered catecholamine transmission would not occur if patients taking phenelzine, a non-selective MAO inhibitor, relapsed and used cocaine."[1] Not cut in stone, but the pharmacology of phenelzine, tranylcypromine, etc... is very complicated, the latter causing a whole host of changes recently elaborated upon.[2]
1 - http://www.ncbi.nlm.nih.gov/pubmed/11245920
2 - http://www.ncbi.nlm.nih.gov/pubmed/16927039
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SNR: XX in that case would be something like the molecule Phenelzine, which binds to the MAO enzyme sites and thus prevents any other molecule from binding to the MAO enzyme, so for example dopamine cannot be broken down by MAO because 80% of MAO enzymes have phenelzine bonded to the MAO enzymes. Are you asking how to DESIGN a molecule that forms a bond to the MAO enzyme?
Epsilon Alpha
Bluelighter
Pretty much need a MAO-B inhibitor brah, so pretty much a PEA with a highly reactive group tacked onto it somewhere preferably towards the N. Or are you asking for stuff to make it less likely to be broken down by MAO? If so an alpha carbon is your best bet, so pretty much an amphetamine is the answer to that (points out retarded duration difference of DOX vs 2C-X)
You could maybe tack on a giant chain substitution on it like MPH, but I really don't think that's where you want to go with this. Same with making it conformationally constrained shit pretty much becomes really different then.
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psood0nym
Bluelighter
I love 4-AcO/ho-DPT but find it is difficult to get into a solution for IMing. How do I easily and conveniently get 4-AcO-DPT fumarate into a solution suitable for intramuscular injection? Alternatively, if I just leave it in sterile water for a few days will that eventually do the trick?
Iodjini_dk
Bluelighter
How about dissolving it in propylene glycol? It will dissolve many compounds which are insoluble in water. However I would expect the fumarate to be quite water soluble. Maybe its contaminated with something that should not be injected in the first place?
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Epsilon Alpha
Bluelighter
Injecting non-quality controlled chemicals really isn't something I'd support. But, warmed sterile saline might be your best option if the stuff dissolves easily which might require some pH tweaking. Pull up some pKa data on it or some closely related compounds and see what it says, might have to add a acid or alkali to it. Buuuuut...
HARM REDUCTION BRAH!
HARM REDUCTION BRAH!
psood0nym
Bluelighter
Thanks for the replies. If I give propylene glycol a shot and it works I'll post back, thanks. I was just hoping someone knew an IMable acid or other product that worked based on some special property of 4-ho-DPT fumerate that caused it to have poor water solubility. I've had 4-AcO-DPT and 4-ho-DPT from ostensibly three sources. It's possible they were all from the same source, but well, there you have it. In any case I've specifically asked for other than the fumerate because of the solubility problems, and was told that the labs were having difficulty keeping it stable in other forms. Shulgin also noted the difficulty in synthesizing 4-ho-DPT in general, so I don't really doubt it. One person in the Big and Dandy thread says it's specifically because it's the fumerate form that it has solubility problems, if that tells you anything.
Anyways, I've tried adding acetic acid, citric acid, and just as an experiment, DMSO -- all with extensive heating. None of them made it water soluble. One person reported success with huge volumes of water, but injecting large volumes is a pain. If it's an impurity that's not dissolving than the impurity makes up a lot of the total weight, yet my insufflated dosage for effects is about what you'd expect for the given oral dosage guidelines (plus the reported success with large volumes of water discounts the impurity theory, too). Oral seems like a waste, and insufflation blows (rectal requires more than insufflation, and so also seems a bit wasteful). IM DPT is the best, and I think it would be for 4-ho-DPT, too, which is why I'm trying to figure it out.
I tried the pKa table but I'm not really super sure what would make a good corollary for 4-ho/AcO-DPT fumerate. 4-AcO-DMT fumerate is water soluble so...
Anyways, I've tried adding acetic acid, citric acid, and just as an experiment, DMSO -- all with extensive heating. None of them made it water soluble. One person reported success with huge volumes of water, but injecting large volumes is a pain. If it's an impurity that's not dissolving than the impurity makes up a lot of the total weight, yet my insufflated dosage for effects is about what you'd expect for the given oral dosage guidelines (plus the reported success with large volumes of water discounts the impurity theory, too). Oral seems like a waste, and insufflation blows (rectal requires more than insufflation, and so also seems a bit wasteful). IM DPT is the best, and I think it would be for 4-ho-DPT, too, which is why I'm trying to figure it out.
I tried the pKa table but I'm not really super sure what would make a good corollary for 4-ho/AcO-DPT fumerate. 4-AcO-DMT fumerate is water soluble so...
sekio
Bluelight Crew
Have you tried adding a small amount of some other water soluble acid (citric? hydrochloric?) and boiling the fuck out of it? I think the issue is that the hydroxytryptamine fumarate salts are just not very soluble and they need a better counterion to go into sol'n nicely.
psood0nym
Bluelighter
I tried heating with both acetic acid and citric acid monohydrate, but did not exactly boil the fuck out of them. I mostly just heated them to pretty hot for about 10 minutes, where the vial got foggy from evaporating water. I suppose I could bust out the hot plate and properly boil the mL or so of water I plan to IM for maybe five minutes to see if that works, thanks. I shattered the bottom of a borosilicate vial using a frying pan recently (I think it was just way too hot too fast), and microwaving makes the water leap out of small vials, so I've resisted vigorous boiling. Both 4-ho-DMT and 4-AcO-DMT fumerate (pretty sure the ho was fumerate at least) have no trouble going into solution in my experience, BTW, but it's worth a shot nevertheless. I will post back if it works (within a few weeks I think).
sekio
Bluelight Crew
Acquire some test tubes or boiling tubes and get a good butane torch lighter. Grab some tongs, add water and your compound and go wild.
I have had success with putting DPT HCl into sol'n by this exact method.
I have had success with putting DPT HCl into sol'n by this exact method.
psood0nym
Bluelighter
^Sounds like a plan, thanks. DPT HCl is a bit of a pain to get into solution, but FYI I've gotten it into solution at 50 mg per mL simply putting the vial on top of my toaster oven and letting the heat from one or two "toasts" get it into solution, without even adding acid. But whatever works. 4-ho-DPT fumerate is MUCH more resistant.
Mr Blonde
Bluelighter
This reminded me of something... I've been using chemicalize.org to get calculations on pKa, log d and other data on various compounds. Is this site considered fairly reliable? I've only just started using it recently, and it seems good so far.
nuke
Bluelighter
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Another thing to try I would guess is a urea and sucrose solution, something like 5%-10% urea and then isotonic concentrations of sucrose with blood... There are old studies in glaucoma patients of 30% urea and 10% sucrose as well, so it's probably safe.
i've read pihkal about 4 times over, and sometimes when i do my crazy ass brainstorming i imagine that i am bouncing ideas off of sasha. tonight i was thinking about how some ligands can bind permanently to receptors. (here, i am assuming that full agonists tend to bind permanently more often than partial agonists, idk for sure if that is true or not).
i had an idea, that it might be possible to get "permanently" bound ligands off the receptor by introducing a second drug that is a competitive partial agonist at that receptor but with a much greater binding affinity than the primary drug in this example. might be rare to find such a molecule, and idk if it is even possible for a drug to have both of those properties, but i feel it is worth pondering over nonetheless.
at first i looked at the problem like sasha would. i wouldn't want to waste time in the laboratory with rats and petri dishes, i would jump straight to self-administered in vivo testing to test such a thing if i thought "permanent" binding had happened to me. in this case, the most immediate means of telling if your experiment had the desired result would be by monitoring your own consciousness as the drug progresses in its action, of course. however, that is far from conclusive. you might be able to monitor your urine and excrement as a means to determine if the experiment was a success or not, but that would be messy. (and no matter what, hopefully you will never actually find yourself in this situation!)
i then had a thought, and asked sasha, "wait, in this case would it actually be much quicker and easier to radiolabel some ligands and test the theory in vitro?"
then i had the thought "god dammit i shouldn't be able to ask a question like that, i haven't even taken organic chemistry yet, i wish i was in school right now." lol
[/insomnia]
[insomniaedit]perhaps would be most effective with multiple administrations, and you may need other methods to induce metabolism or excretion while the bounced pseudo-permanent agonist was in extracellular space. maybe plasmaphersis would be the best choice at this stage (sort of like treating bromism)? once its kicked off the receptor though there would only be a small window of opportunity to get it out of the subject somehow before the second drug is metabolised.
this might be some phizer level pharmacology/biochemistry here i realize
Drugs that permanently bind to receptors is something you do not want to happen. There is a famous case involving this guy Barry Kidston who synthesized a pain killer MPPP but a slight alteration in his procedure resulted in an impurity
of MPTP. Why would this be so bad? Because after injecting his batch, the MPTP permanently bound to his dopamine receptors and gave the 23 year parkinson's like symptoms; in fact, because of his misfortune we figured out the dopamine mechanism of parkinson's.
Remember, your neurons don't always want to be active because the resulting neurotoxins eventually destroy the neurons you wanted to keep "on" forever.
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skillet
Bluelighter
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MPTP doesn't work like that, it's metabolised into MPP+ in the brain, gets taken up by dopaminergic neurons, and kills them.
GPCR's are in a constant flux of being internalised and degraded, and synthesised and transported to the membrane, so though it's possible to permanently attach something to a particular receptor, that receptor doesn't actually last that long.
GPCR's are in a constant flux of being internalised and degraded, and synthesised and transported to the membrane, so though it's possible to permanently attach something to a particular receptor, that receptor doesn't actually last that long.
sekio
Bluelight Crew
"Permanently binding" ligands are no worse than normal, ultra-potent ones. The receptor eventually gets internalised and destroyed.
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