• Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

  • N&PD Moderators: Skorpio

The Big and Bangin' Pseudo-Advanced Drug Chemistry, Pharmacology and More Thread, V.2

Status
Not open for further replies.
Ok, maybe I'm missing something still, but then how do benzodiazepines dissolve in aqueous media if they're sold as the freebase? Also, do they really break open like that? I think not.
 
sekio said:
i thought most BZDs actually were amides that lacked basic nitrogens which could get protonated with the exception of a few (midazolam)... the imide doesn't pick up a proton like a 'normal' amine does, IIRC
Click to expand...

Even midazolam has to be in a low pH solution - any of the triazolo class WILL salt. I know they are way inaccurate, but the Marvinsketch on-line software does allow LogP & PKa so you can look at the different (un)protonated forms against pH. Free to all, knocks out 90% of randoms and gives everyone a leg up on the knowledge base.
 
Dresden said:
Ok, maybe I'm missing something still, but then how do benzodiazepines dissolve in aqueous media if they're sold as the freebase? Also, do they really break open like that? I think not.
Click to expand...

Actually they do... And that irreversible hydrolysis of the benzodiazepinones adder said makes a lot of sense, still don't know why specifically midazolam is chosen though. There is a paper called something like "chemical structure of midazolam compared to other benzodiazepines" if you're still not convinced. Somewhere in it there might be an explanation for the choice of midazolam over triazolo benzos for this application but it's more chemistry than I could understand...
 
I'll take ya'lls word for it. But why bother even cyclizing the benzodiazepines if they're just going to break open to begin working when inside the low pH stomach? I'm confused.

Oh yeah, and seiko I believe you about the law requiring the salt form used be listed on the drug label, and maybe this is the exception that proves the rule, but ibuprofen labels never say anywhere as far as I can tell what salt (or is it the freebase?) of ibuprofen being used in Advil, Motrin, etc. I am thinking it must be the carboxylate sodium salt like naproxen sodium (Aleve), a similar drug, but I really haven't been able to figure that one out, either.
 
ibuprofen labels never say anywhere as far as I can tell what salt (or is it the freebase?) of ibuprofen being used in Advil, Motrin, etc.
Click to expand...

That's because it's just plain ibuprofen as the free acid, it's not a salt.
 
as an aside - Ibuprofen is totally insoluble in water so Vicoprofen should really use the lysine derivative.
 
I think Vicoprofen was invented before the lysine salt came about? For whatever reason ibuprofen is absorbed orally anyway even though it's not water sol. (emulsifiers in bile? alkaline environment in small intestine?) Nevertheless I agree I'd like to see wider usage of ibuprofien lysine.
 
Why is it that in general serotonin releasers (e.g MDMA) are fundamentally less usable long term (and over elongated periods of use eventually lose most of their efficacy) compared to dopamine releasers (e.g. methamphetamine), which can be used continuously for long periods of time, and work with as much efficacy (one doesn't "lose the magic" of meth) ?
 
Do SSRIs like paroxetine actually enter (serotonergic) neurons like SRAs such as MDMA? If not, does the 1,3-benzodiox-5yl part of paroxetine bind analogously to MDMA at SERT?
 
I think that in fact many would say that the "magic" of methamphetamine does wane considerably. The same goes for less damaging stimulants. A lot of the time, people are prescribed a stimulant (ritalin, adderall, vyvsnse) and find in the beginning, they are a lot more social, happy, and fulfilled. As time goes on, these effects wane considerably. And so people think that just because these effects diminish or disappear, that the medication isn't working how it's supposed to. So, for example, while at the start stimulants make things so interesting that very little effort is required to focus, they eventually make it so that it's still easier to focus, but that is requires a considerable greater effort.

I do get that, though, the "magic" of MDMA probably lessesn more than that of more dopaminergic stimulants. Not sure why.
 
When people talk about SRAs having "affinity to SERT", what does this actually mean? Does it suggest that when the SRA binds onto SERT, SERT is reversed? I thought SRAs would have their action similar to amphetamine where they go into the neuron through SERT and then increase cytosolic 5HT concentration, and then through some other mechanism reverse SERT. If all an SRA does is bind onto SERT and either block it (which would make it an SSRI) or reverse it, then where does the cytosolic 5HT come from?
 
The magic of methamphetamine does not wane. I've been using it off but mostly on for 19 years, and the magic as good as ever.

* * *

Why haven't more peptide drugs been developed?
 
If you're talking about neuroactive peptide drugs, well they probably can't cross the gut, let alone the BBB.

On another note, when MAO metabolizes phenethylamine in the brain into phenylacetic acid (more polar), won't the PAA just be stuck in the brain because it can't cross the BBB back into the blood? Thus does MAO serve just to deactivate the neuromodulator rather than excrete it?
 
Hey all

Do more potent(per mg)drugs have the tendency to be less neurotoxic because there is less of the chemical that has to be metabolized(in total weight) or doesnt work it this way.
i know you cant generalize this thesis on all drugs because there just too many drugs with different pharmacological action but im just wondering if its more likewise for a drug to be less neurotoxic if its more potent per mg than say a analog with same effects that is 1/10th of the potency
 
That depends on the cause of the (neuro)toxicity. For example paracetamol hepatotoxicity is dependant on metabolism of paracetamol to NAPQI. Your statement is correct if the drug in its unmetabolized form is itself neurotoxic. However it seems that neurotoxicity seems to correlate with amount of neurotransmission release in some hypotheses. For example a hypothesis for SRA (eg. MDMA) induced serotonergic neurotoxicity is that after all the serotonin is depleted within the neuron, dopamine then enters the serotonergic neuron. If this hypothesis was true then that would mean a more potent drug releasing and depleting more serotonin would cause more neurotoxicity. So in answer to your question it really depends on the mechanism of neurotoxicity.

However, I do think that more potent drugs are theoretically better drugs because they are more likely to be selective to their appropriate target. What I mean by this is: if a drug whose dose was say 10mg interacted with target A and target B, the latter being the desired target, and if an analogue of the drug was found to make it require only 0.1mg for desired effect at target B, then it is unlikely that such a big change will occur at target A, especially if A was vastly different to B, and so 0.1mg will have approximately x100 less effect on A and the same effect on B as 10mg of the other analogue. Thus by making the drug more potent, then by probability you have increased selectivity.

Practically though, especially for recreational drugs, greater potency is bad bad bad, even if the drug has increased selectivity (which could increase therapeutic index eg sufentanyl), as stupid people will be stupid and fuck themselves up. But from a pharmaceutical standpoint it seems good to make a drug more potent, and they can accordingly dose the tablets accordingly, even to small microgram amounts.
 
No simple rule to apply. Nitromethaqualone is x4 as potent as it's parent, but in that para position, it's ripe to be reduced to an amine... and as a very general rule, aromatic amines are bad (BUPO).

The fact that it's all fentanyl analogues and WHICH analogues speaks volumes. These joker have read 'The Seigfried Route' and are not real chemists. Sufentanil is a lot more work. No sign of 3-methyl analogue (Kolokol) so they can't access a wide range of chemicals as does the missing beta hydroxy derivatives. However you read it, I've seen too many good people lose it all to fentanyl. People getting a 20-minute habit where, day & night, they have to take another spray from the solution. One chemist I know was busted & put straight into jail while his assistant wasn't charged but a year later & he's still in withdrawal. Opioids with an N-(aryl)ethyl group bind to a part of the receptor that endorphins don't and by the looks of it, it's a 1-way street. You get a fentanyl habit and no amount of juice is going to fix you. Look at the guy who made etonitazine. That's another strong opiate that binds to that extra point on the receptor. He had money but no amount of juice could fix him... so he killed himself. Worked at Morton Thiokol... Thomas K Highcliff. Etonitazine is only 60x M in man but that's still far, far too much and more evidence that addiction to that class is a 1-way street.
 
clubcard said:
No simple rule to apply. Nitromethaqualone is x4 as potent as it's parent, but in that para position, it's ripe to be reduced to an amine... and as a very general rule, aromatic amines are bad (BUPO).

The fact that it's all fentanyl analogues and WHICH analogues speaks volumes. These joker have read 'The Seigfried Route' and are not real chemists. Sufentanil is a lot more work. No sign of 3-methyl analogue (Kolokol) so they can't access a wide range of chemicals as does the missing beta hydroxy derivatives. However you read it, I've seen too many good people lose it all to fentanyl. People getting a 20-minute habit where, day & night, they have to take another spray from the solution. One chemist I know was busted & put straight into jail while his assistant wasn't charged but a year later & he's still in withdrawal. Opioids with an N-(aryl)ethyl group bind to a part of the receptor that endorphins don't and by the looks of it, it's a 1-way street. You get a fentanyl habit and no amount of juice is going to fix you. Look at the guy who made etonitazine. That's another strong opiate that binds to that extra point on the receptor. He had money but no amount of juice could fix him... so he killed himself. Worked at Morton Thiokol... Thomas K Highcliff. Etonitazine is only 60x M in man but that's still far, far too much and more evidence that addiction to that class is a 1-way street.
Click to expand...
Thanks for the insights!
 
aced126 said:
On another note, when MAO metabolizes phenethylamine in the brain into phenylacetic acid (more polar), won't the PAA just be stuck in the brain because it can't cross the BBB back into the blood? Thus does MAO serve just to deactivate the neuromodulator rather than excrete it?
Click to expand...

I suppose phenylacetic acid is pumped out of the brain via some kind of active transport mechanism? But I never studied in biology as much as I should have. I just really didn't care to subject my brain to all that rote memorization when the rave scene was just starting to burgeon (1996-1997), and I had lots of really good drugs to do. Sad, isn't it?
 
The rave scene began 10 years earlier. I was there...providing 'ambiance' to proceedings. Still have the 1000 capping board.
 
Status
Not open for further replies.
Top