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

[nAON]

^ seems to make sense really. I had a bit of a confusing moment the other day when I was browsing wikipedia and saw things being described as 'silent antagonists', only to realise they've just started using new terminology for regular old (but evidently inaccurate) antagonists.

 

[endotropic]

What are forum members thoughts on this 2014 publishing (pdf file) claiming cocaine & methylphenidate differ from other MAT inhibitors by being "inverse agonists" at the transporter and facilitating release of monoamines thereby?

Essentially, there is an inward and outward facing conformation of DAT, cocaine/MPH binds to the outward facing conformation stabilizing it, and thus causing reverse transport via the inward/outward concentration gradient. The binding site is distinct from that of other reuptake inhibitors, being at TMs 9-11 on DAT whereas other bind to TMs 10-12 (with overlapping loci at 1 & 7).

They put forward an interesting theory but never provide anything beyond circumstantial evidence to support it. If their theory on cocaine's MOA is true that would be great for the drug they're selling by the way.

Their mechanism doesn't really make sense to me either. They claim that cocaine stabilizes an outward conformation of the transporter leading to reverse transport of cytosolic dopamine into the synapse. But where does that cytosolic dopamine come from? Vmat makes sure that dopamine accumulates in vesicles and stays out of the cytosol.

Amphetamine reverse BOTH Vmat and DAT so that DAT has lots of cytosolic dopamine to reverse transport, but the authors of this paper don't give any explanation for where the cytosolic dopamine would come from with cocaine.

 

[Nagelfar]

Amphetamine reverse BOTH Vmat and DAT so that DAT has lots of cytosolic dopamine to reverse transport, but the authors of this paper don't give any explanation for where the cytosolic dopamine would come from with cocaine.

They do touch on that actually, talking about how such an inverse agonist would have a ceiling effect because of its lack of affinity for VMAT.

I think it has to do with influx of Na+ ions from extracellular space. And even though "maximum effect of competitive DAT substrate releasing agents on dopamine efflux is greater
than that of DAT “inverse agonists”" it seems to say neuronal firing is greater (though still reduced) with inverse agonists over substrate releasers (though I can't find where I read that now).

 

[endotropic]

They do touch on that actually, talking about how such an inverse agonist would have a ceiling effect because of its lack of affinity for VMAT.

Right, they discuss how cocaine would have a lower maximum effect than a releasing agent, but not how cocaine could have a greater maximum effect than a standard reuptake inhibitor. My understanding is that Vmat has such a high affinity for Dopamine that cytosolic concentrations stay very low, so even if cocaine can reverse the transporter, what dopamine does it have access to for reverse transport?

I think it has to do with influx of Na+ ions from extracellular space. And even though "maximum effect of competitive DAT substrate releasing agents on dopamine efflux is greater
than that of DAT “inverse agonists”" it seems to say neuronal firing is greater (though still reduced) with inverse agonists over substrate releasers (though I can't find where I read that now).

I think Na+ concentration gradient can help to explain the mechanism of transporter reversal, my question is what possible effect can transporter reversal even have without concurrent Vmat reversal?

Besides, multiple groups have compared the effects of cocaine and other reuptake inhibitors on extracellular dopamine levels, do actual experimental results suggest cocaine can drive more dopamine out of the cell than a standard reuptake inhibitor?

 

[Nagelfar]

...do actual experimental results suggest cocaine can drive more dopamine out of the cell than a standard reuptake inhibitor?

That seems to be what they're saying. Coke & MPH, anyway.

 

[endotropic]

Did they provide a reference where that was actually shown? Or is that just consistent with what they want us to believe about cocaine vs. their product?


edit: I see where they addressed this (briefly): they cite a study that compares methylphenidate to GBR-12909, and show that GBR has a much lower maximum effect than methylphenidate. I don't find that very convincing considering GBR-12909 has been shown to inhibit dopamine release in addition to blocking its reuptake.

 

[ebola?]

GBR-12909 has also been shown to have ceiling-effects in releasing dopamine unique to the compound.

ebola

 

[neurotic]

does 5HT1A agonism play a reasonable role in MDMA's empathogenic effects?

because i was reading this article comparing mephedrone and MDMA (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246659/), and mephedrone also seems like one hell of a serotonin releasing agent too, more potent than MDMA, raising serotonin levels by 940% at 3mg/kg doses, compared to 910% with MDMA at the same doses. but afaik (never tried it) it's not very empathogenic (when compared to MD)

i ask so because i read that 1A agonism supposedly raises oxytocin levels and increases social behaviour in rats as shown by one study with 8-OH-DPAT which is a selective agonist for that receptor

also there doesn't seem to be any instance of mephedrone-induced comedowns as heavy as some of the ones from MDMA, even if apparently people go way overboard with it due to its fiendiness (which btw could be due to simultaneous increased DA levels - much like cocaine -, which MDMA doesn't do as much)... if those severe acute episodes of depression were from 5HT depletion alone, mephedrone should cause it too right?

i guess what i'm asking is, what is the difference between the two here?

i'm curious

 

[Nagelfar]

^Not to jump in front of you and I hope your question gets addressed but I just had a thought/question and it might be quite basic.

It was about Ki ratios, their IC50s etc. Lower is higher binding correct? So a Ki of say 0.00007 is a high affinity, but 150,000 is basically no affinity....

Is there a higher bound in the molecular attraction of any ligand to bind on the largest number possible? Meaning, is there a number (e.g. no affinity, >150,000 or somewhere before/beyond I am assuming) to that value that is basically it has the same amount of affinity to every ligand at that point (which is "none" but a specific number for which I'm asking) and it is as likely to dock with that as any other place in any molecular build? (Somewhat like in quantum its possible for all electrons to shift at once and randomly change gravity or turn air into gold, but its infinitesimally unlikely)

...is there an upper bound where affinity "bottoms up" at a highest number?

Does my question make sense? Is it an entry chemistry school 'everyone knows' type answer perhaps?

 

[Incunabula]

Does anybody know were I can find this Paper by Hoffman online? According to Erowid it's private.

“Pharmacologic Properties and Psychotogenic Effects of some Lysergic Acid Derivatives : Comparison with Delysid (LSD25)”.
Sandoz Internal Publication. 1958;1.

I did google.

 

[Nexus_Tripper]

I call it TCB-3, the 3 specifying the three-carbon chain. It is the amphetamine counterpart of TCB-2.

 

[Incunabula]

I think you meant to post that in the "I like to draw random molecules thread"

Anyway, this is from the TCB-2 thread:

Probably not, because there is not a simple and linear amine chain it is not appropriate anymore to just simply count carbon atoms and call them alpha and beta. Now it is a bicyclic molecule, the main part is the body with 2 rings and it has a mini-"chain" sticking out on the right now with only one carbon. In the main bicyclic body the total number of carbons are counted which makes 8. Then the number of carbon are counted that are between the carbons that unite the rings.

What used to be the alpha is now the 1-position.

There is no corresponding amphetamine because there is no more alpha-position to justify the name amphetamine (= alpha-methyl PEA). If you add a methyl on the 1-position, AFAIK it would probably be constrained (forced) to stick out in a direction that is uncomfortable for binding.
Whether it can be called TCB-3 or not would mostly depend on whether you still find that molecule to be a modification of 2C-B rather than DOB.
IMO what you propose would be appropriately named DOB-CB
The name TCB-3 is not reserved for the cyclopentene analogue, which is called 2CB-Ind so it would be hard to continue the nomenclative series consistently.

I think he has some good points. And any activity, if it's there at all, will probably be less than with TCB-2.

 

[neurotic]

any ideas about the metabolism of the APDB's (dihydrofuran analogs of MD)?

i found an article about APB metabolism but couldn't for the APDB's... i tried searching for other compounds with benzodihydrofuran rings and look up what happened to them but couldnt find anything, i couldnt find any molecule like that that seemed studied anyway... may be you guys know

also would the 3-carboxymethyl-4-hydroxy-amph metabolite of one of the APB's subject to any further metabolism?

 

[Dresden]

Neuropharmacological jargon is largely nonsense, with no application in drug design much.

 

[pharmakos]

i was thinking the other day about the Ouroboros, the archetypal image of the serpent that eats its own tail, and had the thought that a benzene ring is sort of like an Ouroboros, with its constantly shifting resonant state of altering single/double bonds. i checked out the Wikipedia page on Ouroboros, and saw this blurb:

Chemistry

The German organic chemist August Kekulé described the eureka moment when he realized the structure of benzene:

I was sitting, writing at my text-book; but the work did not progress; my thoughts were elsewhere. I turned my chair to the fire and dozed. Again the atoms were gamboling before my eyes. This time the smaller groups kept modestly in the background. My mental eye, rendered more acute by the repeated visions of the kind, could now distinguish larger structures of manifold conformation: long rows, sometimes more closely fitted together; all twining and twisting in snake-like motion. But look! What was that? One of the snakes had seized hold of its own tail, and the form whirled mockingly before my eyes. As if by a flash of lightning I awoke; and this time also I spent the rest of the night in working out the consequences of the hypothesis.

pretty neat

 

[trip407]

Can someone tell me why midazolam is so short acting and has such a low potency compared to clonitrazolam and flubromazolam? Both are much more potent and longer lasting. And i dont see that big of a difference in midazolam and flubromazolam.
Edit: i just recognised, midazolam is not a triazolo compound, so the question is obsolet, sorry.

 

[adder]

I think the question might stand as triazolam is also a short-acting benzodiazepine and it's a triazolo derivative, basically it's 2'-chloroalprazolam. How does the additional chlorine atom impact the half-life? For classic benzodiazepine derivatives ortho-substitution of the phenyl group doesn't always have a positive or negative effect on the half-life, perhaps functional groups at other positions impact the affinity towards CYP enzyme subtypes that mediate hydroxylation of the phenyl ring. It might also be related to the extent different benzodiazepines are bound by proteins. Does anyone know the answer?

 

[AlphaMethylPhenyl]

All right so you guys are probably the most likely to provide a valid answer to this question. Though it may not strictly pertain to pharmacology, "and more" makes it suitable .

I can pop on Google and read all about how selegiline has nootropic potential. It's literally all over. However, there is a painfully small amount of information regarding the other MAOIs and cognition. Okay, so MAOIs may increase feelings of novelty and therefore attention roughly because of increased indirect dopaminergic neurotransmission (even though I found at least one source which points to reuptake inhibition/monoamine release as potential explanations behind some of the mental manifestations of MAOIs). But that doesn't necessarily mean they have nootropic potential. Can someone provide a source which centers on possible cognition-increasing/nootropic action of MAOIs which are treated for depression/anxiety/phobia (as in not rasagiline and not selegiline and not moclobemide because the first and second is not an option and information on selegiline is everywhere).

When it comes down to it, I'd almost rather be unhappy and more intelligent/fast/whatever you want to call it than happy and stupid. It's not like one source would turn my opinion either way, and I know it comes down to individual experience, but I want to see what's out there before I push something past my BBB. Thanks .

 

[Epsilon Alpha]

They put forward an interesting theory but never provide anything beyond circumstantial evidence to support it. If their theory on cocaine's MOA is true that would be great for the drug they're selling by the way.

Their mechanism doesn't really make sense to me either. They claim that cocaine stabilizes an outward conformation of the transporter leading to reverse transport of cytosolic dopamine into the synapse. But where does that cytosolic dopamine come from? Vmat makes sure that dopamine accumulates in vesicles and stays out of the cytosol.

Amphetamine reverse BOTH Vmat and DAT so that DAT has lots of cytosolic dopamine to reverse transport, but the authors of this paper don't give any explanation for where the cytosolic dopamine would come from with cocaine.

My understanding was that it also has some sort of odd effect on the vesicle transport regulatory mechanisms as it leads to more normal exocytosis of dopamine as well
http://www.ncbi.nlm.nih.gov/pubmed/16554471

 

[endotropic]

My understanding was that it also has some sort of odd effect on the vesicle transport regulatory mechanisms as it leads to more normal exocytosis of dopamine as well
http://www.ncbi.nlm.nih.gov/pubmed/16554471

That study suggests a third mechanism for cocaine induced dopamine accumulation independent from its effects on the dopamine transporter (whether reuptake inhibition or inverse agonism).

Basically they claim that cocaine mobilizes a specific pool of vesicles that normally only release in response to continuous action potentials. Then they apply continuous action potentials and see increased synaptic dopamine with cocaine, but to a lesser degree when they knock out the proteins that allow those vesicles to dock. Even if cocaine can mobilize those vesicles directly they would release into the synapse, not the cytosol, so a dopamine transporter working in reverse still wouldn't have access to that dopamine.

If they can show that other DAT blockers don't depend on synapsin expression to increase dopamine then I might believe that cocaine has some special effect on vesicle mobilization, but lacking that negative control I think DAT blockade alone can explain all of the findings outlined in this paper.